Pediatric cancers frequently harbor activating alterations of the RAS signaling pathway. In fusion-negative RMS (FN-RMS), the predominant molecular subtype of rhabdomyosarcoma, 56% of patient tumors carry RAS pathway mutations – with a majority of these tumors harboring Q61X hyperactivating mutations in NRAS or HRAS. We evaluated 16 in vitro RMS models for 32 inhibitors targeting the RAS-RAF-MEK-ERK, PI3K-Akt, or mTOR pathways. RAS(ON) inhibitors RMS-7977 and RMC-6236 (daraxonrasib) emerged as potent, selective agents against NRAS- and HRAS-mutant FN-RMS, including models with trametinib resistance. Treatment suppressed of MEK and ERK phosphorylation and reduced DUSP6 expression. Daraxonrasib also induced expression of differentiation markers, confirmed by bulk RNA-sequencing and immunofluorescence. To define mechanisms of adaptation to RAS(ON) inhibition, we performed single-cell RNA-sequencing combined with intracellular protein staining using oligo-conjugated antibodies. Two persistent subpopulations were identified that restore Akt and MEK phosphorylation during therapy. Combination drug-screening revealed that vertical co-inhibition of RAS signaling with Akt or MEK blockade may overcome these adaptive states. Using perturbation sequencing, a method that integrates scRNA-seq with pooled CRISPR screening, we assessed the impact of 199 gene knockdowns on cellular heterogeneity in NRAS Q61H- and HRAS Q61K-mutant FN-RMS. Eight transcription factors whose knockout selectively depleted drug-tolerant cell states, were identified. We are now evaluating in vitro and in vivo efficacy of genetic and pharmacologic blockade of these eight targets in combination with RAS(ON) inhibition. Moreover, we are extending these approaches to additional RAS-driven pediatric cancers. Citation Format: Roketa Henry, Ayush Attery, Anang Shelat, Anand Patel. Overcoming treatment adaptation to RAS(ON) inhibition in NRAS/HRAS mutant pediatric tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1): nr B049.
{"title":"Abstract B049: Overcoming treatment adaptation to RAS(ON) inhibition in NRAS/HRAS mutant pediatric tumors","authors":"Roketa Henry, Ayush Attery, Anang Shelat, Anand Patel","doi":"10.1158/1538-7445.rasoncother26-b049","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-b049","url":null,"abstract":"Pediatric cancers frequently harbor activating alterations of the RAS signaling pathway. In fusion-negative RMS (FN-RMS), the predominant molecular subtype of rhabdomyosarcoma, 56% of patient tumors carry RAS pathway mutations – with a majority of these tumors harboring Q61X hyperactivating mutations in NRAS or HRAS. We evaluated 16 in vitro RMS models for 32 inhibitors targeting the RAS-RAF-MEK-ERK, PI3K-Akt, or mTOR pathways. RAS(ON) inhibitors RMS-7977 and RMC-6236 (daraxonrasib) emerged as potent, selective agents against NRAS- and HRAS-mutant FN-RMS, including models with trametinib resistance. Treatment suppressed of MEK and ERK phosphorylation and reduced DUSP6 expression. Daraxonrasib also induced expression of differentiation markers, confirmed by bulk RNA-sequencing and immunofluorescence. To define mechanisms of adaptation to RAS(ON) inhibition, we performed single-cell RNA-sequencing combined with intracellular protein staining using oligo-conjugated antibodies. Two persistent subpopulations were identified that restore Akt and MEK phosphorylation during therapy. Combination drug-screening revealed that vertical co-inhibition of RAS signaling with Akt or MEK blockade may overcome these adaptive states. Using perturbation sequencing, a method that integrates scRNA-seq with pooled CRISPR screening, we assessed the impact of 199 gene knockdowns on cellular heterogeneity in NRAS Q61H- and HRAS Q61K-mutant FN-RMS. Eight transcription factors whose knockout selectively depleted drug-tolerant cell states, were identified. We are now evaluating in vitro and in vivo efficacy of genetic and pharmacologic blockade of these eight targets in combination with RAS(ON) inhibition. Moreover, we are extending these approaches to additional RAS-driven pediatric cancers. Citation Format: Roketa Henry, Ayush Attery, Anang Shelat, Anand Patel. Overcoming treatment adaptation to RAS(ON) inhibition in NRAS/HRAS mutant pediatric tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1): nr B049.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1158/0008-5472.can-25-1992
Utsarga Adhikary,Bethany Tesar,Kamal Patel,Michael J Schmidt,Hannah R Levy,Eva Zacharakis,Marina Godes,Prafulla C Gokhale,Kyle M Hebert,Donna S Neuberg,Gregory H Bird,Loren D Walensky
Relapsed and refractory cancers effectively overcome diverse modalities of cancer treatment, whose principal targets are nucleic acids and proteins. The plasma membranes of cancer cells represent an alternative and underutilized target, with the potential for membrane lysis to induce rapid, pro-inflammatory cell death that circumvents the challenges of intratumor heterogeneity and immune evasion. Here, we repurposed StAMP51.2, a stapled magainin 2 peptide previously optimized for selective membrane lysis of gram-negative bacteria, to target cancer cell membranes. The PRISM assay, a high throughput cancer cytotoxicity screen, revealed cancer cells most vulnerable to StAMP51.2 and biomarkers of susceptibility, specifically reduced cholesteryl esters and elevated triacylglycerols. This signature was validated in pairs of sensitive (OCI-AML3, THP-1) and resistant (K562, KSM-11) leukemia cell lines, with their differential responses correlated to distinct lipidomic profiles. Susceptibility of OCI-AML3 cells in culture extended to the in vivo context, where StAMP51.2 suppressed leukemic growth in orthotopic and intraperitoneal models. To further characterize the mechanism of action, StAMP51.2-resistant OCI-AML3 cells were generated, which required four months of low-level exposure. Strikingly, drug-resistant OCI-AML3 cells recapitulated the lipidomic phenotype of naturally resistant K562 cells. Transcriptomic analyses further revealed that lipid reprogramming was accompanied by pervasive downregulation of inflammatory signaling. Thus, in advancing StAMP51.2 as an oncolytic prototype, this study uncovered an immune regulatory axis that links membrane integrity to inflammatory signaling.
{"title":"Cancer Susceptibility to Stapled Oncolytic Peptides is Dictated by Membrane Cholesterol and Inflammatory Signaling.","authors":"Utsarga Adhikary,Bethany Tesar,Kamal Patel,Michael J Schmidt,Hannah R Levy,Eva Zacharakis,Marina Godes,Prafulla C Gokhale,Kyle M Hebert,Donna S Neuberg,Gregory H Bird,Loren D Walensky","doi":"10.1158/0008-5472.can-25-1992","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1992","url":null,"abstract":"Relapsed and refractory cancers effectively overcome diverse modalities of cancer treatment, whose principal targets are nucleic acids and proteins. The plasma membranes of cancer cells represent an alternative and underutilized target, with the potential for membrane lysis to induce rapid, pro-inflammatory cell death that circumvents the challenges of intratumor heterogeneity and immune evasion. Here, we repurposed StAMP51.2, a stapled magainin 2 peptide previously optimized for selective membrane lysis of gram-negative bacteria, to target cancer cell membranes. The PRISM assay, a high throughput cancer cytotoxicity screen, revealed cancer cells most vulnerable to StAMP51.2 and biomarkers of susceptibility, specifically reduced cholesteryl esters and elevated triacylglycerols. This signature was validated in pairs of sensitive (OCI-AML3, THP-1) and resistant (K562, KSM-11) leukemia cell lines, with their differential responses correlated to distinct lipidomic profiles. Susceptibility of OCI-AML3 cells in culture extended to the in vivo context, where StAMP51.2 suppressed leukemic growth in orthotopic and intraperitoneal models. To further characterize the mechanism of action, StAMP51.2-resistant OCI-AML3 cells were generated, which required four months of low-level exposure. Strikingly, drug-resistant OCI-AML3 cells recapitulated the lipidomic phenotype of naturally resistant K562 cells. Transcriptomic analyses further revealed that lipid reprogramming was accompanied by pervasive downregulation of inflammatory signaling. Thus, in advancing StAMP51.2 as an oncolytic prototype, this study uncovered an immune regulatory axis that links membrane integrity to inflammatory signaling.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"42 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1158/1538-7445.rasoncother26-a027
Adrien Grimont, David J. Falvo, Whitney J. Sisso, Paul Zumbo, Francisco Santos, Christopher W. Chan, William B. Fall, Grace Pan, Yinuo Meng, Katherine Ferrick, Megan Cleveland, Maria Paz Zafra, Tomer M. Yaron, Andre F. Rendeiro, Erika Hissong, Rhonda K. Yantiss, Doron Betel, Mark A. Magnuson, Steven D. Leach, Anil K. Rustgi, Lukas E. Dow, Rohit Chandwani
Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant Kras in the formation of pancreatic cancer (PDAC). How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement novel Ptf1a-TdTomato mice and multiple KRAS mutants across an array of genetic, pharmacologic, and inflammatory perturbations in vivo. Whereas KRASG12D co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRASG12R/V can initiate but not sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. We find the KRASG12R/V defects consist of a failure to invoke robust EGFR signaling and an inability to drive the transcription and epigenetic remodeling of the key tuft cell transcription factor Pou2f3 and the RAC1 GEF Vav1. These in turn lead to a defect in RAC1 signaling and downstream remodeling of the actin cytoskeleton critical to pancreatic intraepithelial neoplasia (PanIN) development. To address the contexts in which KRASG12R could give rise to robust tumorigenesis, we incorporated genetic and pharmacologic perturbations in vivo to inactivate one or two copies of p53, to modulate MAPK/ERK signaling, or to enforce active RAC1. Whereas none of these models could enforce KRASG12R-driven tumor initiation, we found that only constitutive AKT activation in vivo was sufficient to rescue both RAC1 signaling and the tumorigenic potential of KRASG12R. Corroborating these findings, we observe in the human context an enrichment of PI3K pathway mutations specifically in KRASG12R-mutant PDAC. These data underscore that lineage plasticity is facilitated by all three Kras mutants but neoplastic commitment depends significantly on the precise mutation in Kras. As the marked heterogeneity among KRAS variants begins early in tumorigenesis, our findings are crucial in delineating there are mutation-specific oncogenic trajectories that should in turn direct the implementation of KRAS-directed therapeutics and early detection strategies in patients. Citation Format: Adrien Grimont, David J. Falvo, Whitney J. Sisso, Paul Zumbo, Francisco Santos, Christopher W. Chan, William B. Fall, Grace Pan, Yinuo Meng, Katherine Ferrick, Megan Cleveland, Maria Paz Zafra, Tomer M. Yaron, Andre F. Rendeiro, Erika Hissong, Rhonda K. Yantiss, Doron Betel, Mark A. Magnuson, Steven D. Leach, Anil K. Rustgi, Lukas E. Dow, Rohit Chandwani. Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1): nr A027.
胰腺炎症驱动腺泡到导管化生（ADM），这是一种类似于祖细胞的状态，可以被突变的Kras劫持，形成胰腺癌（PDAC）。这些细胞命运的决定如何根据KRAS突变而变化仍然知之甚少。为了定义突变特异性谱系逆转和肿瘤起始，我们在体内通过一系列遗传、药理学和炎症扰动，对新型Ptf1a-TdTomato小鼠和多个KRAS突变体进行了实验。KRASG12D选择损伤来实现谱系逆转、增强子重编程和肿瘤启动，而KRASG12R/V可以启动但不能维持去分化和肿瘤转录和表观遗传程序。我们发现KRASG12R/V缺陷包括不能激活强大的EGFR信号，不能驱动关键簇状细胞转录因子Pou2f3和RAC1 GEF Vav1的转录和表观遗传重塑。这些反过来导致RAC1信号的缺陷和对胰腺上皮内瘤变（PanIN）发展至关重要的肌动蛋白细胞骨架的下游重塑。为了解决KRASG12R可能导致强大肿瘤发生的背景，我们在体内结合遗传和药理学扰动来灭活一个或两个p53拷贝，调节MAPK/ERK信号，或强制激活RAC1。虽然这些模型都不能强制KRASG12R驱动的肿瘤启动，但我们发现体内只有组成型AKT激活足以挽救RAC1信号和KRASG12R的致瘤潜能。为了证实这些发现，我们在人类环境中观察到PI3K通路突变的富集，特别是在krasg12r突变的PDAC中。这些数据强调，所有三种Kras突变体都促进了谱系的可塑性，但肿瘤承受性在很大程度上取决于Kras的精确突变。由于KRAS变异之间的显著异质性在肿瘤发生早期就开始了，我们的研究结果对于描述突变特异性的致癌轨迹至关重要，这些轨迹应该反过来指导KRAS定向治疗的实施和患者的早期检测策略。引文格式：Adrien Grimont， David J. Falvo, Whitney J. Sisso, Paul Zumbo, Francisco Santos, Christopher W. Chan, William B. Fall, Grace Pan， Yinuo b孟，Katherine Ferrick, Megan Cleveland, Maria Paz Zafra, Tomer M. Yaron, Andre F. renreniro, Erika Hissong, Rhonda K. Yantiss, Doron Betel, Mark A. Magnuson, Steven D. Leach, Anil K. Rustgi, Lukas E. Dow, Rohit Chandwani。分子动力学驱动KRAS突变体在胰腺肿瘤发生中的表型差异[摘要]。摘自：AACR癌症研究特别会议论文集：RAS肿瘤发生和治疗；2026年3月5-8日；费城（PA）： AACR；巨蟹座Res 2026；86(5_Suppl_1): nr A027。
{"title":"Abstract A027: Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis","authors":"Adrien Grimont, David J. Falvo, Whitney J. Sisso, Paul Zumbo, Francisco Santos, Christopher W. Chan, William B. Fall, Grace Pan, Yinuo Meng, Katherine Ferrick, Megan Cleveland, Maria Paz Zafra, Tomer M. Yaron, Andre F. Rendeiro, Erika Hissong, Rhonda K. Yantiss, Doron Betel, Mark A. Magnuson, Steven D. Leach, Anil K. Rustgi, Lukas E. Dow, Rohit Chandwani","doi":"10.1158/1538-7445.rasoncother26-a027","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-a027","url":null,"abstract":"Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant Kras in the formation of pancreatic cancer (PDAC). How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement novel Ptf1a-TdTomato mice and multiple KRAS mutants across an array of genetic, pharmacologic, and inflammatory perturbations in vivo. Whereas KRASG12D co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRASG12R/V can initiate but not sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. We find the KRASG12R/V defects consist of a failure to invoke robust EGFR signaling and an inability to drive the transcription and epigenetic remodeling of the key tuft cell transcription factor Pou2f3 and the RAC1 GEF Vav1. These in turn lead to a defect in RAC1 signaling and downstream remodeling of the actin cytoskeleton critical to pancreatic intraepithelial neoplasia (PanIN) development. To address the contexts in which KRASG12R could give rise to robust tumorigenesis, we incorporated genetic and pharmacologic perturbations in vivo to inactivate one or two copies of p53, to modulate MAPK/ERK signaling, or to enforce active RAC1. Whereas none of these models could enforce KRASG12R-driven tumor initiation, we found that only constitutive AKT activation in vivo was sufficient to rescue both RAC1 signaling and the tumorigenic potential of KRASG12R. Corroborating these findings, we observe in the human context an enrichment of PI3K pathway mutations specifically in KRASG12R-mutant PDAC. These data underscore that lineage plasticity is facilitated by all three Kras mutants but neoplastic commitment depends significantly on the precise mutation in Kras. As the marked heterogeneity among KRAS variants begins early in tumorigenesis, our findings are crucial in delineating there are mutation-specific oncogenic trajectories that should in turn direct the implementation of KRAS-directed therapeutics and early detection strategies in patients. Citation Format: Adrien Grimont, David J. Falvo, Whitney J. Sisso, Paul Zumbo, Francisco Santos, Christopher W. Chan, William B. Fall, Grace Pan, Yinuo Meng, Katherine Ferrick, Megan Cleveland, Maria Paz Zafra, Tomer M. Yaron, Andre F. Rendeiro, Erika Hissong, Rhonda K. Yantiss, Doron Betel, Mark A. Magnuson, Steven D. Leach, Anil K. Rustgi, Lukas E. Dow, Rohit Chandwani. Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1): nr A027.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1158/1538-7445.rasoncother26-ia011
Kevin Shannon
NRAS mutations are prevalent in acute myeloid leukemia (AML), juvenile myelomonocytic leukemia (JMML), melanoma, and thyroid cancer. Ras proteins are dependent on post-translational lipid modifications. While K-Ras4b farnesylation is sufficient for stable association with the plasma membrane (PM), farnesylated H-Ras, K-Ras4a, and N-Ras undergo palmitoylation before regulated translocation to the PM. N-Ras palmitoylation by palmitoyl acyl transferases and depalmitoylation by ABHD17 serine hydrolasess is a dynamic process. We hypothesized that co-targeting ABHD17 enzymes and the mitogen activated protein kinase (MAPK) pathway would exhibit chemical synthetic lethality in NRAS-mutant AML. ABD957 is an in vitro active ABHD17 inhibitor synthesized and characterized by Drs. Micah Niphakis (Lundbeck, Inc) and Benjamin Cravatt (Scripps Research Institute) that reduced the growth of NRAS mutant AML cells and was synergistic with the MEK inhibitor PD0325901 (PD901) (Remsberg et al, Nat Chem Biol 2021; 8:856-864). ABD778 is an analog of ABD957 with drug-like pharmacologic properties. ABD778 blocked N-Ras depalmitoylation in pulse-chase experiments (EC50 ∼53 nM), showed selective target engagement of ABHD17 enzymes, and induced sustained ABHD17 inhibition after in vivo dosing. ABD778 showed nanomolar potency - but incomplete growth inhibition - in NRAS-mutant AML cell lines (Emax ∼50%) but had no effect on KRAS-mutant AML cells. ABD778 and PD901 synergistically inhibited the growth of NRAS-mutant AML cell lines, which correlated with MAPK suppression. We confirmed these data in isogenic MOLM-14 AML cell line models that are dependent on oncogenic N-Ras or K-Ras proteins. Biochemical and BRET analyses support a working model whereby ABD778 reduces oncogenic N-Ras signal output and blunts the adaptive feedback response of RAS-mutant cancer cells to MEK inhibition. ABD778 also potently and selectively inhibited myeloid progenitor colony growth from primary NRAS-mutant JMMLs. ABD778 modestly extended the survival of mice transplanted with primary mouse AMLs harboring an Nras G12D driver mutation. Recipients of these Nras-mutant AMLs treated with ABD778 and PD901 had twice the median survival of mice dosed with PD901 alone (40 versus 20 days, p<0.0001). We observed no single-agent or combination activity of ABD778 in control Kras G12D AMLs. Mice that were continuously treated with ABD778/PD901 died from progressive leukemia. Exome sequencing of refractory leukemias uncovered on-pathway mutations in Kras A146T and Braf G466E that caused adaptive resistance to ABD778/PD901. Additional studies revealed synergistic growth inhibition by ABD778 and other Ras/MAPK pathway inhibitors NRAS-dependent AML cell lines models and showed that ABD778 restored sensitivity in a patient-derived xenograft FLT3- and NRAS-mutant model of gilteritinib resistance These studies validate ABHD17 enzymes and – more broadly - post-translational N-Ras processing is a novel druggable vu
{"title":"Abstract IA011: Targeting the Palmitoylation Cycle in NRAS -Mutant Cancers","authors":"Kevin Shannon","doi":"10.1158/1538-7445.rasoncother26-ia011","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-ia011","url":null,"abstract":"NRAS mutations are prevalent in acute myeloid leukemia (AML), juvenile myelomonocytic leukemia (JMML), melanoma, and thyroid cancer. Ras proteins are dependent on post-translational lipid modifications. While K-Ras4b farnesylation is sufficient for stable association with the plasma membrane (PM), farnesylated H-Ras, K-Ras4a, and N-Ras undergo palmitoylation before regulated translocation to the PM. N-Ras palmitoylation by palmitoyl acyl transferases and depalmitoylation by ABHD17 serine hydrolasess is a dynamic process. We hypothesized that co-targeting ABHD17 enzymes and the mitogen activated protein kinase (MAPK) pathway would exhibit chemical synthetic lethality in NRAS-mutant AML. ABD957 is an in vitro active ABHD17 inhibitor synthesized and characterized by Drs. Micah Niphakis (Lundbeck, Inc) and Benjamin Cravatt (Scripps Research Institute) that reduced the growth of NRAS mutant AML cells and was synergistic with the MEK inhibitor PD0325901 (PD901) (Remsberg et al, Nat Chem Biol 2021; 8:856-864). ABD778 is an analog of ABD957 with drug-like pharmacologic properties. ABD778 blocked N-Ras depalmitoylation in pulse-chase experiments (EC50 ∼53 nM), showed selective target engagement of ABHD17 enzymes, and induced sustained ABHD17 inhibition after in vivo dosing. ABD778 showed nanomolar potency - but incomplete growth inhibition - in NRAS-mutant AML cell lines (Emax ∼50%) but had no effect on KRAS-mutant AML cells. ABD778 and PD901 synergistically inhibited the growth of NRAS-mutant AML cell lines, which correlated with MAPK suppression. We confirmed these data in isogenic MOLM-14 AML cell line models that are dependent on oncogenic N-Ras or K-Ras proteins. Biochemical and BRET analyses support a working model whereby ABD778 reduces oncogenic N-Ras signal output and blunts the adaptive feedback response of RAS-mutant cancer cells to MEK inhibition. ABD778 also potently and selectively inhibited myeloid progenitor colony growth from primary NRAS-mutant JMMLs. ABD778 modestly extended the survival of mice transplanted with primary mouse AMLs harboring an Nras G12D driver mutation. Recipients of these Nras-mutant AMLs treated with ABD778 and PD901 had twice the median survival of mice dosed with PD901 alone (40 versus 20 days, p&lt;0.0001). We observed no single-agent or combination activity of ABD778 in control Kras G12D AMLs. Mice that were continuously treated with ABD778/PD901 died from progressive leukemia. Exome sequencing of refractory leukemias uncovered on-pathway mutations in Kras A146T and Braf G466E that caused adaptive resistance to ABD778/PD901. Additional studies revealed synergistic growth inhibition by ABD778 and other Ras/MAPK pathway inhibitors NRAS-dependent AML cell lines models and showed that ABD778 restored sensitivity in a patient-derived xenograft FLT3- and NRAS-mutant model of gilteritinib resistance These studies validate ABHD17 enzymes and – more broadly - post-translational N-Ras processing is a novel druggable vu","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"31 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1158/1538-7445.rasoncother26-pr016
Jason Z. Zhang
RAS proto-oncogenes encode four major isoforms with substantial sequence homology and similar in vitrobiochemical properties. There is considerable interest in investigating the roles of these proteins independently as their association with different cancers vary, but there are few Ras isoform-specific binding reagents because the only significant sequence differences are in their disordered and highly charged C-termini, which have been difficult to elicit antibodies against. To overcome this limitation, we use deep learning-based methods to design Ras isoform-specific binders (RIBs) for all major Ras isoforms de novo by targeting the Ras C-terminus. The RIBs bind to their target Ras isoforms both in vitro and in cells with remarkable specificity, disrupting their membrane localization, and inhibiting Ras activity. Used as specific inhibitors, the RIBs helped dissect the distinct roles of Ras isoforms during RasG12C inhibitor resistance, illuminating their utility in understanding Ras biology and disease and suggesting potential therapeutic applications. Overall, this study demonstrates the utility of designing proteins as chemical biology tools for understanding basic biology. Citation Format: Jason Z. Zhang. De novo design of Ras isoform selective binders [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1): nr PR016.
RAS原癌基因编码四种主要亚型，它们具有大量的序列同源性和相似的体外生化特性。由于这些蛋白与不同癌症的关联各不相同，因此人们对独立研究这些蛋白的作用非常感兴趣，但很少有Ras亚型特异性结合试剂，因为唯一显著的序列差异是在它们的无序和高度带电的c端，这很难引发抗体。为了克服这一限制，我们使用基于深度学习的方法，通过靶向Ras c端，为所有主要的Ras亚型从头设计Ras亚型特异性结合物（rib）。在体外和细胞中，rib都以显著的特异性结合其靶Ras亚型，破坏其膜定位并抑制Ras活性。作为特异性抑制剂，rib有助于分析Ras亚型在RasG12C抑制剂耐药过程中的独特作用，阐明了它们在理解Ras生物学和疾病方面的效用，并提出了潜在的治疗应用。总的来说，这项研究证明了设计蛋白质作为理解基础生物学的化学生物学工具的效用。引用格式：Jason Z. Zhang。Ras异构体选择性结合剂的从头设计[摘要]。摘自：AACR癌症研究特别会议论文集：RAS肿瘤发生和治疗；2026年3月5-8日；费城（PA）： AACR；巨蟹座Res 2026；86(5_Suppl_1): nr PR016。
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Pub Date : 2026-03-05DOI: 10.1158/1538-7445.rasoncother26-b029
Niloofar Khairkhah, Ali Namvar, Mostafa M H. Ibrahim, Emily L. Lasse-Opsahl, Carlos E. Espinoza, Megan Faunce, Lily Rober, Marina Pasca di Magliano, Stefanie Galban
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer deaths in the U.S. KRAS mutations are among the most common oncogenic drivers, with two distinct mutations (G12C and G12D) being the most prevalent in smokers and non-smokers, respectively. This distinct expression has been linked to therapeutic responses, especially to immune checkpoint inhibitors (ICIs). Importantly, CD274/PD-L1 expression varies in the two subtypes, likely explaining different responses to ICI, which shows little efficacy in KRASG12D-mutant tumors. A deeper understanding of how KRASG12D shapes the tumor microenvironment (TME) and how KRAS inhibition interfaces with ICI therapy is needed to guide more effective treatment strategies. Using a KRASG12D genetically engineered mouse model, we have shown that genetic KRASG12D inhibition modulates immunosuppression and immune checkpoint expression in myeloid cells (Lasse-Opsahl & Barravecchia et al., JCI Insight 2025). Here, we tested the pan-RAS inhibitor RMC-7977 for 5 days at 10 mg/kg/day in this L-iKRASG12D model. Single-cell RNA sequencing revealed that RMC-7977 significantly increased the percentage (∼36%) of neutrophils expressing PD-L1 but did not affect neutrophil abundance, indicating strong adaptive PD-L1–mediated resistance, and providing rationale for combining RMC-7977 with anti–PD-L1 ICI. Interestingly, when we tested co-targeted therapy (RMC-7977 + anti-PD-L1 [6.7 mg/kg]), we observed no significant change in the percentage of neutrophils expressing PD-L1, but did see a reduction in neutrophil abundance, suggesting additional alterations in the TME. To assess therapeutic efficacy of this combination, we used an orthotopic KRASG12D lung cancer model derived from the L-iKRASG12D model. Consistent with our prior observations, genetic KRASG12D inhibition combined with anti–PD-L1 significantly extended survival. In contrast, pharmacological KRAS inhibition (RMC-7977) combined with anti–PD-L1 did not show a survival benefit. These results suggest that RMC-7977 may activate a distinct resistance mechanism from genetic KRAS inhibition that limits therapeutic durability. However, longer pharmacological intervention may be needed to achieve survival benefit with ICI. Unlike genetic inhibition, which maintains stable pathway suppression, pharmacologic intervention is temporary, allowing persister cells to regain KRAS signaling after discontinuing treatment. Future studies will assess whether sequential dosing with a KRAS inhibitor plus anti–PD-L1 prevents tumor recurrence. In conclusion, our findings show that KRASG12D inhibition reshapes the TME by increasing the percentage of PD-L1+ neutrophils and reducing overall neutrophil abundance when combined with anti–PD-L1 therapy. Our survival study further suggests that achieving sustained KRAS inhibition may be necessary for combination with ICI to achieve clinical benefit, though we acknowledge that prolonged dosing may be limited by toxicities. These insights
非小细胞肺癌（NSCLC）仍然是美国癌症死亡的主要原因，KRAS突变是最常见的致癌驱动因素之一，两种不同的突变（G12C和G12D）分别在吸烟者和非吸烟者中最普遍。这种独特的表达与治疗反应有关，特别是对免疫检查点抑制剂（ICIs）。重要的是，CD274/PD-L1在两种亚型中的表达不同，可能解释了ICI对krasg12d突变肿瘤的不同反应。需要更深入地了解KRASG12D如何塑造肿瘤微环境（TME）以及KRAS抑制如何与ICI治疗相结合，以指导更有效的治疗策略。通过KRASG12D基因工程小鼠模型，我们发现KRASG12D基因抑制可调节骨髓细胞的免疫抑制和免疫检查点表达（Lasse-Opsahl &； Barravecchia等人，JCI Insight 2025）。在这里，我们在L-iKRASG12D模型中以10 mg/kg/天的剂量对泛ras抑制剂rmmc -7977进行了5天的测试。单细胞RNA测序显示，rmmc -7977显著增加了表达PD-L1的中性粒细胞百分比（~ 36%），但不影响中性粒细胞丰度，表明PD-L1介导的强适应性耐药性，并为rmmc -7977联合抗PD-L1 ICI提供了理论依据。有趣的是，当我们测试联合靶向治疗（rmmc -7977 +抗PD-L1 [6.7 mg/kg]）时，我们观察到表达PD-L1的中性粒细胞百分比没有显著变化，但中性粒细胞丰度确实减少，这表明TME有额外的改变。为了评估这种组合的治疗效果，我们使用了来自l - ikkrasg12d模型的原位KRASG12D肺癌模型。与我们之前的观察一致，KRASG12D基因抑制联合抗pd - l1显著延长了生存期。相比之下，药理学KRAS抑制（rmmc -7977）联合抗pd - l1并没有显示出生存获益。这些结果表明，rmmc -7977可能激活了一种不同的抗性机制，而这种机制可能限制了KRAS基因抑制的治疗持久性。然而，可能需要更长时间的药物干预才能获得ICI的生存益处。与维持稳定通路抑制的遗传抑制不同，药物干预是暂时的，允许持续性细胞在停止治疗后重新获得KRAS信号。未来的研究将评估KRAS抑制剂加抗pd - l1序贯给药是否能预防肿瘤复发。总之，我们的研究结果表明，KRASG12D抑制通过增加PD-L1+中性粒细胞的百分比和降低总体中性粒细胞丰度来重塑TME，当与抗PD-L1治疗联合使用时。我们的生存研究进一步表明，实现持续的KRAS抑制可能是与ICI联合获得临床益处所必需的，尽管我们承认长时间给药可能受到毒性的限制。这些见解可能为优化或顺序KRASi-ICI策略提供潜在信息，以防止肿瘤复发。引文格式：Niloofar Khairkhah， Ali Namvar, Mostafa M h Ibrahim, Emily L. lase - opsahl, Carlos E. Espinoza, Megan Faunce, Lily Rober, Marina Pasca di Magliano, Stefanie Galban。免疫检查点介导的KRASG12D抑制耐药性[摘要]。摘自：AACR癌症研究特别会议论文集：RAS肿瘤发生和治疗；2026年3月5-8日；费城（PA）： AACR；巨蟹座Res 2026；86(5_sup_1): nr B029。
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Pub Date : 2026-03-05DOI: 10.1158/1538-7445.rasoncother26-pr005
Mark M. Awad, Biagio Ricciuti, Sandra Vietti Michelina, Edoardo Garbo, Paolo Tarantino, Alok Tewari, Igor Odintsov, Xinan Wang, Cassio Murilo Trovo Hidalgo Filho, Nishant Gandhi, Kenneth Kehl, Giuseppe Lamberti, Alessandro Di Federico, Malini Gandhi, Federica Pecci, Mihaela Aldea, Valentina Santo, Eleonora Gariazzo, Lynette Sholl, Stefano Scalera, Marcello Maugeri, Nancy Lin, Federico Cappuzzo, Pasi Janne, Steven Ressler, Marzia Capelletti, Alexa Schrock, Toni Choueiri, Julie Wiese, Debbie Liao, Shailaja Kasibhatla, Sara Tolaney, Andrew Aguirre, Alice Shaw, Chiara Ambrogio
KRAS mutations are established oncogenic drivers and resistance mechanisms, but the biological and clinical significance of KRAS gene amplification (KRASAMP) is poorly understood. Here, we integrate genomic, structural, clinical, and functional data to show that KRASAMP is a recurrent de novo driver alteration and therapeutic vulnerability across human cancers. In three independent clinico-genomic datasets totaling 685,507 tumors, KRASAMP occurred in ∼2-3% of cancers, with enrichment in esophagogastric, germ cell, ovarian, non-small cell lung, colorectal, biliary tract, pancreatic, and breast cancers. High-level KRASAMP was largely mutually exclusive with canonical oncogenic drivers, and increasing KRAS copy number inversely correlated with the prevalence of alternative drivers, supporting KRASAMP as an independent oncogenic event. KRAS copy gains tightly correlated with increased KRAS mRNA and protein expression and with poorer overall survival across tumor types, irrespective of KRAS mutation status. Whole-genome sequencing and FISH revealed heterogeneous amplicon architectures, including extrachromosomal DNA and linear chromosomal configurations. In Rasless cells, forced overexpression of wild-type KRAS alone restored MAPK signaling, rescued proliferation, and conferred sensitivity to the mutation-agnostic pan-RAS inhibitor RMC-7977. These data establish KRAS amplification as a de novo, targetable oncogenic driver in human cancer. Citation Format: Mark M. Awad, Biagio Ricciuti, Sandra Vietti Michelina, Edoardo Garbo, Paolo Tarantino, Alok Tewari, Igor Odintsov, Xinan Wang, Cassio Murilo Trovo Hidalgo Filho, Nishant Gandhi, Kenneth Kehl, Giuseppe Lamberti, Alessandro Di Federico, Malini Gandhi, Federica Pecci, Mihaela Aldea, Valentina Santo, Eleonora Gariazzo, Lynette Sholl, Stefano Scalera, Marcello Maugeri, Nancy Lin, Federico Cappuzzo, Pasi Janne, Steven Ressler, Marzia Capelletti, Alexa Schrock, Toni Choueiri, Julie Wiese, Debbie Liao, Shailaja Kasibhatla, Sara Tolaney, Andrew Aguirre, Alice Shaw, Chiara Ambrogio. KRAS amplification as de novo oncogenic alteration and therapeutic target in human cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1): nr PR005.
KRAS突变是确定的致癌驱动因素和耐药机制，但KRAS基因扩增（KRASAMP）的生物学和临床意义尚不清楚。在这里，我们整合了基因组、结构、临床和功能数据，表明KRASAMP是人类癌症中一种复发性的从头驱动改变和治疗易感性。在总共685,507个肿瘤的三个独立临床基因组数据集中，KRASAMP出现在约2-3%的癌症中，在食管胃、生殖细胞、卵巢癌、非小细胞肺、结直肠癌、胆道癌、胰腺癌和乳腺癌中富集。高水平KRASAMP与典型的致癌驱动因素在很大程度上是相互排斥的，KRAS拷贝数的增加与替代驱动因素的患病率呈负相关，支持KRASAMP作为一个独立的致癌事件。无论KRAS突变状态如何，KRAS拷贝增益与KRAS mRNA和蛋白表达的增加密切相关，并且与肿瘤类型中较差的总生存率密切相关。全基因组测序和FISH揭示了异质扩增子结构，包括染色体外DNA和线性染色体构型。在无Rasless细胞中，强行过表达野生型KRAS可以恢复MAPK信号，挽救增殖，并赋予对突变不可知的泛ras抑制剂rmmc -7977的敏感性。这些数据表明KRAS扩增在人类癌症中是一种全新的、可靶向的致癌驱动因素。引文格式:马克·m·阿瓦德、比亚吉奥·里丘蒂、桑德拉·维耶蒂·米切丽娜、爱德华多·嘉宝、保罗·塔伦蒂诺、阿洛克·特瓦里、伊戈尔·奥丁索夫、王希南、卡西奥·穆里洛·特罗沃·伊达尔戈·菲略、尼桑特·甘地、肯尼斯·凯尔、朱塞佩·兰贝蒂、亚历山德罗·迪·费德里科、马里尼·甘地、费代丽卡·佩奇、米哈埃拉·阿尔迪亚、瓦伦蒂娜·桑托、埃莱奥诺拉·加里佐、莱内特·肖尔、斯蒂法诺·斯卡莱拉、马塞洛·毛盖里、南希·林、费德里科·卡普佐、帕西·珍妮、史蒂文·雷斯勒、玛齐亚·卡佩莱蒂、亚历克莎·施罗克、托尼·乔埃里、朱莉·维泽、Debbie Liao, Shailaja Kasibhatla, Sara Tolaney, Andrew Aguirre, Alice Shaw, Chiara Ambrogio。KRAS扩增作为人类癌症的新发致癌改变和治疗靶点[摘要]。摘自：AACR癌症研究特别会议论文集：RAS肿瘤发生和治疗；2026年3月5-8日；费城（PA）： AACR；巨蟹座Res 2026；86(5_Suppl_1): nr PR005。
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Pub Date : 2026-03-05DOI: 10.1158/1538-7445.rasoncother26-a016
Patrick Pfaff, Kevan Shokat
Tricomplex inhibitors (TCIs) represent a new class of direct Ras inhibitors that engage the active, GTP-loaded Ras(on) state through recruitment of Cyclophilin A. Daraxonrasib (RMC-6236) is a pan-Ras TCI which has been recently reported to restore intrinsic GTPase activity of G12-mutant Ras isoforms. Structural analysis of a pan-Ras TCI bound to K-Ras(GDP–AlF3) reveals a transition-state arrangement of Tyr32 and Gln61 that closely mirrors endogenous GTPase–GAP complexes. This includes a closed Switch-I conformation engaging the cis-GTPase machinery in a manner analogous to non-arginine-finger GAPs such as RanGAP. These observations position pan-Ras TCIs as pharmacologic GAP mimetics. The engagement of K-Ras(GTP) by first generation Switch-II pocket K-Ras inhibitors, including the approved GDP-state selective K-Ras G12C inhibitor adagrasib (MRTX-849), is kinetically constrained by slow endogenous hydrolysis of the mutant GTPase. The GTPase-promoting activity of daraxonrasib therefore suggests synergy with adagrasib and other Switch-II pocket inhibitors by enriching the more sensitive GDP-state. We demonstrate that daraxonrasib sensitizes K-Ras(GTP) G12C to covalent adagrasib labeling in both recombinant protein and cellular context. In K-Ras G12C and G12D mutant cell lines, combinations of daraxonrasib with adagrasib or HRS-4642 (MRTX-1133 analog) yield accelerated K-Ras engagement, rapid p-ERK suppression, and significant Loewe synergy scores in viability assays. These findings establish GAP mimetics as rational and potent combination partners for SW-II inhibitors. The synergistic combination has potential to deepen and prolong pathway suppression while enabling dose reductions that may mitigate on-target toxicity and resistance. Citation Format: Patrick Pfaff, Kevan Shokat. GAP mimetics display synergy with K-Ras Switch-II inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1): nr A016.
{"title":"Abstract A016: GAP mimetics display synergy with K-Ras Switch-II inhibition","authors":"Patrick Pfaff, Kevan Shokat","doi":"10.1158/1538-7445.rasoncother26-a016","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-a016","url":null,"abstract":"Tricomplex inhibitors (TCIs) represent a new class of direct Ras inhibitors that engage the active, GTP-loaded Ras(on) state through recruitment of Cyclophilin A. Daraxonrasib (RMC-6236) is a pan-Ras TCI which has been recently reported to restore intrinsic GTPase activity of G12-mutant Ras isoforms. Structural analysis of a pan-Ras TCI bound to K-Ras(GDP–AlF3) reveals a transition-state arrangement of Tyr32 and Gln61 that closely mirrors endogenous GTPase–GAP complexes. This includes a closed Switch-I conformation engaging the cis-GTPase machinery in a manner analogous to non-arginine-finger GAPs such as RanGAP. These observations position pan-Ras TCIs as pharmacologic GAP mimetics. The engagement of K-Ras(GTP) by first generation Switch-II pocket K-Ras inhibitors, including the approved GDP-state selective K-Ras G12C inhibitor adagrasib (MRTX-849), is kinetically constrained by slow endogenous hydrolysis of the mutant GTPase. The GTPase-promoting activity of daraxonrasib therefore suggests synergy with adagrasib and other Switch-II pocket inhibitors by enriching the more sensitive GDP-state. We demonstrate that daraxonrasib sensitizes K-Ras(GTP) G12C to covalent adagrasib labeling in both recombinant protein and cellular context. In K-Ras G12C and G12D mutant cell lines, combinations of daraxonrasib with adagrasib or HRS-4642 (MRTX-1133 analog) yield accelerated K-Ras engagement, rapid p-ERK suppression, and significant Loewe synergy scores in viability assays. These findings establish GAP mimetics as rational and potent combination partners for SW-II inhibitors. The synergistic combination has potential to deepen and prolong pathway suppression while enabling dose reductions that may mitigate on-target toxicity and resistance. Citation Format: Patrick Pfaff, Kevan Shokat. GAP mimetics display synergy with K-Ras Switch-II inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1): nr A016.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1158/1538-7445.rasoncother26-pr007
Silvia Coma, Brandon L. Mouery, Ryan D. Mouery, Clint A. Stalnecker, Fusheng Zhou, Adrienne D. Cox, Channing J. Der, Jonathan A. Pachter
KRAS G12D is the most prevalent KRAS mutation in human cancers, mutated in 40%, 15%, and 5% of pancreatic, colorectal and lung cancers, respectively. VS-7375 (GFH375) is an oral, selective KRAS G12D dual ON/OFF inhibitor exhibiting extremely high affinity (KD = 12-18 pM) and long residence time (18-24 hours) for the ON and OFF states of human KRAS G12D. In KRAS G12D-mutated (mt) xenograft models representing pancreatic, colorectal and lung cancers, VS-7375 has shown potent single agent anti-tumor efficacy with oral dosing. To assess potential benefits of dual ON/OFF inhibition relative to ON-only RAS inhibitors, we compared VS-7375 relative to the KRAS G12D-ON inhibitor zoldonrasib (RMC-9805) in tumor cell signaling assays. In KRAS G12D mt cells in vitro, VS-7375 strongly reduced pERK at concentrations as low as 1 nM at 4 hours and was durable through 48 hours. In contrast, substantial inhibition of pERK by the KRAS G12D-ON inhibitor zoldonrasib (RMC-9805) was not evident until 24 hours and required 30-fold higher concentration. Additionally, 1 nM of VS-7375 durably suppressed pAKT, pS6 and MYC signaling, while suppression of these markers by zoldonrasib required higher concentrations. We further compared efficacy of VS-7375 relative to zoldonrasib and the pan-RAS ON-only inhibitor daraxonrasib (RMC-6236) in KRAS G12D mt in vivo models. In the KP4 KRAS G12D mt pancreatic cancer model, VS-7375 showed similar initial tumor regression relative to zoldonrasib and daraxonrasib. However, by approximately 20 days of dosing with continuous dosing of all agents, zoldonrasib and daraxonrasib progressively lost their anti-tumor activity with associated tumor outgrowth (mean tumor volume >850 mm3 by day 30) in contrast to those treated with VS-7375 which showed sustained tumor regression (mean tumor volume ∼80 mm3 by day 30). Accordingly, pharmacodynamic analysis with pathway-specific gene signatures showed that whereas all three KRAS inhibitors inhibited ERK, MYC and PI3K signaling at day 6, only the G12D ON/OFF inhibitor VS-7375 maintained inhibition of these signaling pathways by day 20. VS-7375 also showed deeper tumor regression compared to these RAS ON-only inhibitors in KRAS G12D mt lung and colorectal xenograft models. Additionally, we assessed combination of VS-7375 with other targeted agents. In KRAS G12D mt colorectal models, the combination of VS-7375 with cetuximab induced strong tumor growth inhibition. Furthermore, in the KP4 pancreatic cancer model (KRAS G12D mt; MTAP deleted), while VS-7375 single agent induced strong tumor regression lasting through day 40, the combination of VS-7375 with a PRMT5 inhibitor induced strong tumor regression lasting through 100 days of dosing. VS-7375 is currently undergoing clinical evaluation as monotherapy and in combination with cetuximab, chemotherapy, or chemotherapy + pembrolizumab for patients with KRAS G12D-mutated cancers in the US (VS-7375-101; NCT07020221) and in China (NCT06500676). Citation
KRAS G12D是人类癌症中最普遍的KRAS突变，分别在40%、15%和5%的胰腺癌、结直肠癌和肺癌中发生突变。VS-7375 （GFH375）是一种口服选择性KRAS G12D双开/关抑制剂，具有极高的亲和力（KD = 12-18 pM）和对人KRAS G12D开/关状态的长停留时间（18-24小时）。在代表胰腺癌、结直肠癌和肺癌的KRAS g12d突变（mt）异种移植模型中，VS-7375在口服剂量下显示出强大的单药抗肿瘤疗效。为了评估双重ON/OFF抑制相对于ON-only RAS抑制剂的潜在益处，我们比较了VS-7375与KRAS G12D-ON抑制剂zoldonrasib （rmmc -9805）在肿瘤细胞信号分析中的作用。在体外KRAS G12D mt细胞中，VS-7375在低至1 nM的浓度下，在4小时内强烈降低pERK，并持续48小时。相比之下，KRAS G12D-ON抑制剂zoldonrasib （RMC-9805）对pERK的实质性抑制直到24小时才明显，并且需要30倍的浓度。此外，1 nM的VS-7375持续抑制pAKT、pS6和MYC信号，而zoldonrasib对这些标记物的抑制需要更高的浓度。我们进一步比较了VS-7375在KRAS G12D mt体内模型中相对于zoldonrasib和pan-RAS ON-only抑制剂daraxonrasib （rmmc -6236）的疗效。在KP4 KRAS G12D mt胰腺癌模型中，VS-7375相对于唑多拉西布和daraxonrasib表现出相似的初始肿瘤消退。然而，在所有药物连续给药约20天后，zoldonrasib和daraxonrasib逐渐失去了抗肿瘤活性，并伴有相关的肿瘤生长（到第30天平均肿瘤体积为850 mm3），而接受VS-7375治疗的患者则显示出持续的肿瘤消退（到第30天平均肿瘤体积为80 mm3）。因此，具有途径特异性基因特征的药效学分析显示，尽管所有三种KRAS抑制剂在第6天抑制ERK， MYC和PI3K信号通路，但只有G12D ON/OFF抑制剂VS-7375在第20天保持对这些信号通路的抑制作用。在KRAS G12D肺和结直肠癌异种移植模型中，VS-7375比这些RAS ON-only抑制剂显示出更深的肿瘤消退。此外，我们评估了VS-7375与其他靶向药物的联合使用。在KRAS G12D mt结直肠癌模型中，VS-7375联合西妥昔单抗对肿瘤生长有较强的抑制作用。此外，在KP4胰腺癌模型（KRAS G12D mt； MTAP缺失）中，VS-7375单药可诱导持续40天的强肿瘤消退，VS-7375联合PRMT5抑制剂可诱导持续100天的强肿瘤消退。VS-7375目前正在美国（VS-7375-101; NCT07020221）和中国（NCT06500676）接受KRAS g12d突变癌症患者的单药治疗和联合西妥昔单抗、化疗或化疗+派姆单抗的临床评估。引用格式：Silvia Coma， Brandon L. Mouery, Ryan D. Mouery, Clint A. Stalnecker, Fusheng Zhou, Adrienne D. Cox, Channing J. Der, Jonathan A. Pachter。选择性口服KRAS G12D双开/关抑制剂VS-7375单用及联用靶向药物的抗肿瘤疗效[摘要]。摘自：AACR癌症研究特别会议论文集：RAS肿瘤发生和治疗；2026年3月5-8日；费城（PA）： AACR；巨蟹座Res 2026；86(5_Suppl_1): nr PR007。
{"title":"Abstract PR007: Anti-tumor efficacy of the selective oral KRAS G12D dual ON/OFF inhibitor VS-7375 as a single agent and in combination with targeted agents","authors":"Silvia Coma, Brandon L. Mouery, Ryan D. Mouery, Clint A. Stalnecker, Fusheng Zhou, Adrienne D. Cox, Channing J. Der, Jonathan A. Pachter","doi":"10.1158/1538-7445.rasoncother26-pr007","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-pr007","url":null,"abstract":"KRAS G12D is the most prevalent KRAS mutation in human cancers, mutated in 40%, 15%, and 5% of pancreatic, colorectal and lung cancers, respectively. VS-7375 (GFH375) is an oral, selective KRAS G12D dual ON/OFF inhibitor exhibiting extremely high affinity (KD = 12-18 pM) and long residence time (18-24 hours) for the ON and OFF states of human KRAS G12D. In KRAS G12D-mutated (mt) xenograft models representing pancreatic, colorectal and lung cancers, VS-7375 has shown potent single agent anti-tumor efficacy with oral dosing. To assess potential benefits of dual ON/OFF inhibition relative to ON-only RAS inhibitors, we compared VS-7375 relative to the KRAS G12D-ON inhibitor zoldonrasib (RMC-9805) in tumor cell signaling assays. In KRAS G12D mt cells in vitro, VS-7375 strongly reduced pERK at concentrations as low as 1 nM at 4 hours and was durable through 48 hours. In contrast, substantial inhibition of pERK by the KRAS G12D-ON inhibitor zoldonrasib (RMC-9805) was not evident until 24 hours and required 30-fold higher concentration. Additionally, 1 nM of VS-7375 durably suppressed pAKT, pS6 and MYC signaling, while suppression of these markers by zoldonrasib required higher concentrations. We further compared efficacy of VS-7375 relative to zoldonrasib and the pan-RAS ON-only inhibitor daraxonrasib (RMC-6236) in KRAS G12D mt in vivo models. In the KP4 KRAS G12D mt pancreatic cancer model, VS-7375 showed similar initial tumor regression relative to zoldonrasib and daraxonrasib. However, by approximately 20 days of dosing with continuous dosing of all agents, zoldonrasib and daraxonrasib progressively lost their anti-tumor activity with associated tumor outgrowth (mean tumor volume &gt;850 mm3 by day 30) in contrast to those treated with VS-7375 which showed sustained tumor regression (mean tumor volume ∼80 mm3 by day 30). Accordingly, pharmacodynamic analysis with pathway-specific gene signatures showed that whereas all three KRAS inhibitors inhibited ERK, MYC and PI3K signaling at day 6, only the G12D ON/OFF inhibitor VS-7375 maintained inhibition of these signaling pathways by day 20. VS-7375 also showed deeper tumor regression compared to these RAS ON-only inhibitors in KRAS G12D mt lung and colorectal xenograft models. Additionally, we assessed combination of VS-7375 with other targeted agents. In KRAS G12D mt colorectal models, the combination of VS-7375 with cetuximab induced strong tumor growth inhibition. Furthermore, in the KP4 pancreatic cancer model (KRAS G12D mt; MTAP deleted), while VS-7375 single agent induced strong tumor regression lasting through day 40, the combination of VS-7375 with a PRMT5 inhibitor induced strong tumor regression lasting through 100 days of dosing. VS-7375 is currently undergoing clinical evaluation as monotherapy and in combination with cetuximab, chemotherapy, or chemotherapy + pembrolizumab for patients with KRAS G12D-mutated cancers in the US (VS-7375-101; NCT07020221) and in China (NCT06500676). Citation","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"63 3 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1158/1538-7445.rasoncother26-a017
Lorenzo Tomassoni, Alvaro Curiel-Garcia, Harika Gundlapalli, Melina Chen, Urszula Wasko-Kornberg, Ximo Pechuan-Jorge, Rashi Raghulan, Yongxian Zhuang, Kevin Contrepois, Steven A. Sastra, Carmine F. Palermo, Ida Aronchik, Jingjing Jiang, Andrea Califano, Mallika Singh, Kenneth P. Olive
Multiple studies have demonstrated preclinical activity of RAS inhibitors in models of pancreatic ductal adenocarcinoma (PDAC) and early results from ongoing clinical trials show promise. Following our earlier work using RMC-7977 (a preclinical tool compound related to the investigational RAS(ON) multi-selective inhibitor daraxonrasib) in a broad range of preclinical models, we elected to study the impact of RAS(ON) inhibition and standard-of-care (SOC) cytotoxic chemotherapies on the heterogeneity of malignant cells in PDAC. We performed single cell RNA sequencing (scRNAseq) on over three dozen PDAC tumors from the KPC genetically engineered mouse model, using different treatments and timepoints, yielding over a quarter million high quality single cell expression profiles. Consistent with prior studies, we found that RMC-7977 preferentially depleted more poorly differentiated malignant cells from KPC pancreatic tumors by one week of treatment. Residual malignant cells were well differentiated and showed hyperactivation of distinct sets of gastrointestinal and pancreatic progenitor transcription factors. Spatial transcriptomics on the same KPC tumors validated these findings and elucidated clear histological associations with RAS inhibitor treatment. This phenotype was also validated in human tissue explant models using surrogate immunohistochemical markers of cell states. We then decided to investigate the molecular, cellular, and preclinical consequences of combining RAS(ON)-Multi inhibitors with SOC chemotherapy agents. We first employed the well-validated OncoTreat algorithm to predict which PDAC malignant cells may be most susceptible to different SOC agents. Strikingly, we found that nearly all SOC agents were inferred to preferentially target more well-differentiated malignant cells. Indeed, we found that treatment of tumor-bearing KPC mice with gemcitabine + nab-paclitaxel (GnP) led to a depletion of well-differentiated malignant cell states, as measured by single cell regulatory network analysis. This led us to hypothesize that combining RAS inhibition with SOC agents might target complementary sets of malignant cell states, forming a rational basis for combining these agents. Indeed, preclinical intervention studies combining daraxonrasib with GnP showed combinatorial activity in a range of xenograft, syngeneic allograft, and patient-derived xenograft models of PDAC. Ongoing studies in the KPC model system will directly assess the impacts of these combination regimens on malignant PDAC cell states and will directly address the roles of cellular plasticity versus selective cell death in the modulation of cell state in response to RAS inhibition. Together these studies inform the rationale for the combination of RAS(ON) inhibition with cytotoxic chemotherapies in PDAC. Citation Format: Lorenzo Tomassoni, Alvaro Curiel-Garcia, Harika Gundlapalli, Melina Chen, Urszula Wasko-Kornberg, Ximo Pechuan-Jorge, Rashi Raghulan, Yongxian Zhuang, Kevi
多项研究已经证明RAS抑制剂在胰腺导管腺癌（PDAC）模型中的临床前活性，并且正在进行的临床试验的早期结果显示出希望。根据我们早期在广泛的临床前模型中使用rmmc -7977（一种与正在研究的RAS（ON）多选择性抑制剂daraxonrasib相关的临床前工具化合物）的工作，我们选择研究RAS（ON）抑制和标准护理（SOC）细胞毒性化疗对PDAC恶性细胞异质性的影响。我们对来自KPC基因工程小鼠模型的30多个PDAC肿瘤进行了单细胞RNA测序（scRNAseq），使用不同的处理方法和时间点，产生了超过25万个高质量的单细胞表达谱。与先前的研究一致，我们发现rmmc -7977在治疗一周后优先清除KPC胰腺肿瘤中分化较差的恶性细胞。残留的恶性细胞分化良好，并表现出不同的胃肠道和胰腺祖细胞转录因子的过度激活。相同KPC肿瘤的空间转录组学证实了这些发现，并阐明了与RAS抑制剂治疗的明确组织学关联。使用细胞状态的替代免疫组织化学标记物在人体组织移植模型中也验证了这种表型。然后，我们决定研究RAS(ON)-Multi抑制剂联合SOC化疗药物的分子、细胞和临床前后果。我们首先使用经过验证的OncoTreat算法来预测哪些PDAC恶性细胞可能对不同的SOC药物最敏感。引人注目的是，我们发现几乎所有的SOC制剂都被推断优先靶向分化程度较高的恶性细胞。事实上，我们发现，通过单细胞调节网络分析，用吉西他滨+ nab-紫杉醇（GnP）治疗荷瘤KPC小鼠导致分化良好的恶性细胞状态的消失。这使我们假设RAS抑制与SOC药物联合可能针对互补组的恶性细胞状态，形成这些药物联合的合理基础。事实上，联合daraxonrasib与GnP的临床前干预研究显示，在一系列异种移植物、同基因异体移植物和患者来源的PDAC异种移植模型中，daraxonrasib具有联合活性。KPC模型系统中正在进行的研究将直接评估这些联合方案对恶性PDAC细胞状态的影响，并将直接解决细胞可塑性与选择性细胞死亡在响应RAS抑制的细胞状态调节中的作用。总之，这些研究为PDAC中RAS（ON）抑制与细胞毒性化疗的结合提供了理论依据。引文格式：Lorenzo Tomassoni， Alvaro curiela - garcia, Harika Gundlapalli, Melina Chen, Urszula Wasko-Kornberg, Ximo Pechuan-Jorge, Rashi Raghulan, Yongxian Zhuang, Kevin Contrepois, Steven A. Sastra, Carmine F. Palermo, Ida Aronchik, jingjingjiang, Andrea Califano, Mallika Singh, Kenneth P. Olive。RAS抑制和细胞毒性化疗靶向胰腺癌的互补细胞状态[摘要]。摘自：AACR癌症研究特别会议论文集：RAS肿瘤发生和治疗；2026年3月5-8日；费城（PA）： AACR；巨蟹座Res 2026；86(5_Suppl_1): nr A017。
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