Cancer research最新文献

{"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 >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}

{"title":"Abstract A017: RAS inhibition and cytotoxic chemotherapy target complementary cell states in pancreatic cancer","authors":"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","doi":"10.1158/1538-7445.rasoncother26-a017","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-a017","url":null,"abstract":"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","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"93 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358867","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}

{"title":"Abstract B017: Mechanisms regulating resistance to KRAS inhibitors driven by ΔNp63 in lung adenocarcinoma","authors":"Santanu Adhikary, Marco Napoli, Suehelay Acevedo Acevedo, Christina L. Carr, Jaden R. Baldwin, Nicole Hackel, Hitendra S. Solanki, Yaakov E. Stern, LaxmiSwetha Karanam, Duy T. Nguyen, Eric B. Haura, Elsa R. Flores","doi":"10.1158/1538-7445.rasoncother26-b017","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-b017","url":null,"abstract":"Therapies targeting mutant KRAS have been a successful strategy for the treatment of lung adenocarcinoma (LuAD). The major challenges lie when these tumors acquire resistance to these KRAS inhibitors (KRASi). Recent studies have identified various mechanisms via which these tumors become resistant to the drugs, including histological transition from adeno to squamous cell carcinoma. Genetic mutations in TP53 are one of the leading causes of drug resistance. Mutations in TP53 lead to the inhibition of the tumor and metastasis suppressor TAp63 and stabilization of the oncogenic isoform ΔNp63. In PDAC, it is reported that ΔNp63 drives the adeno to squamous transition. We have previously shown that loss of ΔNp63 in a KRAS G12D-driven LuAD leads to fewer tumors and of lower grade. Here we report that cells and tumors resistant to KRAS G12C inhibitors show elevated levels of ΔNp63 compared to the sensitive cells and tumors. We performed a ChIP-seq assay to identify the molecular targets regulated by ΔNp63 in driving resistance to KRASi. We identified genes involved in pathways like drug resistance, metabolism, cell adhesion, KRAS signaling, cellular mechanics, and GPCRs, that are bound by ΔNp63 in KRASiR cells. Interestingly, we also found enrichment of ΔNp63 at the NRF2 promoter in the resistant cells. The KRASiR cells exhibited increased glycolysis, mitochondrial fission, and a lower mitochondrial membrane potential, which reverted upon loss of ΔNp63. We elucidated that ΔNp63 is crucial for driving resistance to the KRAS G12C inhibitor (AMG510, also known as sotorasib) in vivo via adeno to squamous transition. Loss of ΔNp63 induces apoptosis and resensitizes the resistant tumors to AMG510. We also found that ΔNp63 drives resistance to other RAS inhibitors, including the RAS-MULTI-ON inhibitor (RMC6236). We further showed that ΔNp63 is crucial for driving resistance to AMG510 in genetically engineered mouse models, depending on the mutation status of TP53, and in patients treated with sotorasib. Therefore, targeting ΔNp63 can be a novel approach to overcome the acquired resistance to KRAS inhibitors. Citation Format: Santanu Adhikary, Marco Napoli, Suehelay Acevedo Acevedo, Christina L. Carr, Jaden R. Baldwin, Nicole Hackel, Hitendra S. Solanki, Yaakov E. Stern, LaxmiSwetha Karanam, Duy T. Nguyen, Eric B. Haura, Elsa R. Flores. Mechanisms regulating resistance to KRAS inhibitors driven by ΔNp63 in lung adenocarcinoma [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 B017.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"4 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358871","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}

{"title":"Abstract A031: A metabolic weak spot: GJB3–SLC7A11 Synthetic lethality in colon cancer","authors":"Disha Acharya, Balkrishna Chaube, Sudhanshu Shukla","doi":"10.1158/1538-7445.rasoncother26-a031","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-a031","url":null,"abstract":"Colon adenocarcinoma frequently harbors activating KRAS mutations (∼35–45%), which are associated with aggressive disease, poor prognosis, and resistance to anti-EGFR therapies. Oncogenic KRAS constitutively activates downstream effector signaling, particularly the RAS–RAF–MEK–ERK cascade, driving uncontrolled proliferation and survival. As direct targeting of KRAS remains clinically limited, identifying downstream effectors and context-specific vulnerabilities is essential for developing alternative therapeutic strategies. Methods Publicly available colorectal cancer gene expression datasets from GEO were analyzed to identify KRAS-regulated genes through comparisons of KRAS-mutant and wild-type samples. Dependency and expression data from DepMap were used to assess context-specific vulnerabilities. Colorectal cancer cell lines were subjected to lentiviral shRNA-mediated silencing of GJB3 and SLC7A11, individually or in combination, with knockdown confirmed by qPCR and immunoblotting. Proliferation, migration, and anchorage-independent growth were assessed using standard functional assays. RNA sequencing following GJB3 silencing was performed to identify altered stress and metabolic pathways. FRA1 binding to the GJB3 promoter was assessed by ChIP-PCR, and gap junction–mediated cystine transfer was evaluated using metabolite transport assays. AI-based language tools were used to assist with grammar and clarity during manuscript preparation. Results Analysis of GEO datasets identified GJB3 as one of the most strongly upregulated genes in KRAS-mutant colorectal cancers. GJB3 expression positively correlated with KRAS signaling, and mechanistic studies demonstrated direct transcriptional regulation by the KRAS-controlled transcription factor FRA1, establishing GJB3 as a downstream KRAS effector. Functional assays revealed that GJB3 silencing significantly impaired proliferation, migration, and spheroid formation. Transcriptomic profiling following GJB3 depletion showed activation of the integrated stress response, marked by GCN2 signaling, indicating metabolic stress. As GJB3 encodes the gap junction protein connexin-31, we demonstrated that cystine is transferred through CX31-mediated gap junctions. Dependence on this pathway was cell line–specific: GJB3-dependent cells such as SW480 exhibited low expression of the canonical cystine transporter SLC7A11, whereas SLC7A11-high cell lines (HCT116, HT29) were resistant to GJB3 loss. Importantly, dual silencing of GJB3 and SLC7A11 induced a strong synthetic lethal effect in otherwise GJB3-independent cells. Conclusion These findings identify GJB3 as a previously unrecognized KRAS effector that supports colorectal cancer growth through gap junction–mediated cystine uptake. Variable SLC7A11 expression dictates reliance on GJB3, revealing a context-dependent metabolic vulnerability. Targeting the GJB3–SLC7A11 cystine uptake axis represents a potential therapeutic strategy for KRAS-driven colorectal cancers r","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"52 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358918","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}

{"title":"Abstract A025: Unveiling Synergistic Potential of VHL and KEAP1-based PROTACs for Targeted Protein Degradation","authors":"Sehbanul Islam","doi":"10.1158/1538-7445.rasoncother26-a025","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-a025","url":null,"abstract":"Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules bridging a target protein with an E3 ubiquitin ligase, promoting its ubiquitylation and degradation. Unlike traditional inhibitors, PROTACs exploit transient interactions, enabling the selective degradation of “undruggable” proteins, thereby expanding the landscape of druggable targets. However, PROTACs are not without limitations. The “hook effect”—a phenomenon where high PROTAC concentrations reduce efficacy due to inactive binary complex formation—compromises their clinical utility. Additionally, single PROTACs may fail to achieve complete degradation due to insufficient polyubiquitination or suboptimal E3 ligase recruitment, limiting their therapeutic efficacy. These challenges highlight the need for strategies to enhance PROTAC performance and so therapeutic applicability. In this study, we introduce a novel dual-PROTAC strategy that recruits two distinct E3 ligases, such as KEAP1 and VHL, to cooperatively degrade KRAS(G12D) and Androgen Receptor (AR). Our data demonstrate that combining KEAP1- and VHL-recruiting PROTACs synergistically enhances target degradation, reduces the required dosing, and minimizes off-target effects. Notably, KEAP1 recruitment offers the unique advantage to favour polyubiquitin chains elongation, thereby improving proteasomal recognition. In conclusion, dual-targeting approach represents a promising avenue for optimizing PROTAC-based therapeutics. Citation Format: Sehbanul Islam. Unveiling Synergistic Potential of VHL and KEAP1-based PROTACs for Targeted Protein Degradation [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 A025.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"43 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358924","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}

{"title":"Abstract A048: Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors","authors":"Daniel A. Bonsor, Lorenzo I. Finci, Jacob R. Potter, Lucy C. Young, Vanessa E. Wall, Ruby Goldstein de Salazar, Katie R. Geis, Tyler Stephens, Joseph Finney, Dwight V. Nissley, Frank McCormick, Dhirendra K. Simanshu","doi":"10.1158/1538-7445.rasoncother26-a048","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-a048","url":null,"abstract":"RAF activation is a critical step in MAPK signaling and requires both RAS engagement and dephosphorylation of a conserved phosphoserine by the SHOC2–RAS–PP1C complex. MRAS forms a high-affinity SHOC2–MRAS–PP1C (SMP) assembly, whereas canonical RAS isoforms (KRAS, HRAS, NRAS) create analogous complexes with lower affinity. Despite this, tumors driven by oncogenic KRAS, HRAS, or NRAS remain highly dependent on SHOC2, indicating that these weaker assemblies are functionally relevant for tumorigenesis. To investigate how canonical RAS proteins assemble into lower-affinity ternary complexes, we determined the cryo-EM structure of the SHOC2–KRAS–PP1C (SKP) complex, stabilized by Noonan syndrome-associated mutations. The SKP complex resembles the SMP architecture but engages fewer contacts and buries less surface area due to the absence of MRAS-specific structural elements that enhance stability. RAS inhibitors MRTX1133 and RMC-6236 reshape Switch-I/II regions, preventing SKP assembly more efficiently than they disrupt preformed complexes, while leaving SMP formation unaffected because they do not target MRAS. Given that MRAS is upregulated in KRAS inhibitor resistance, we characterize an MRAS variant that binds MRTX1133; although capable of forming SMP, its assembly is blocked by the inhibitor, highlighting the potential for dual targeting of SKP and SMP complexes. Collectively, these results reveal isoform-specific determinants of SHOC2–RAS–PP1C formation and provide a rationale for simultaneously inhibiting both SKP and SMP to counter resistance in RAS-driven cancers. Citation Format: Daniel A. Bonsor, Lorenzo I. Finci, Jacob R. Potter, Lucy C. Young, Vanessa E. Wall, Ruby Goldstein de Salazar, Katie R. Geis, Tyler Stephens, Joseph Finney, Dwight V. Nissley, Frank McCormick, Dhirendra K. Simanshu. Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors [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 A048.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"200 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358804","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}

{"title":"Abstract B026: RAF1 gene amplification drives RAS inhibitor resistance via nuclear translocation and interactions with PLK1 and Aurora A kinases","authors":"Hitendra S. Solanki, Denis Imbody, Bina Desai, Andriy Marusyk, Eric B. Haura","doi":"10.1158/1538-7445.rasoncother26-b026","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-b026","url":null,"abstract":"Emerging data from clinical trials suggests that mechanisms that reactivate the MAPK pathway via gene amplification events can drive resistance to RAS inhibitors. This includes amplification of KRAS itself, as well as RAF1, RICTOR , and MYC. How amplification events affect signaling networks and the implications for therapeutic opportunities to overcome resistance remain unclear. To model this, we employed RMC-7977, a RAS(ON) multi-selective inhibitor structurally related to the clinical candidate daraxonrasib (RMC-6236), and established a RMC-7977–resistant (RMC-7977-R) H358 isogenic model that exhibit RAF1 amplification, as confirmed by amplicon-level analysis of whole-exome sequencing (WES), western blotting, and RNA sequencing. We evaluated this resistant cell line responses to a panel of RAS pathway–targeting agents, including RAF inhibitors (LXH-254 and exarafenib), MEK1/2 PROTAC degrader (MS934), pan-RAF-MEK non-degrading molecular glue (NST-628), RAF/MEK clamp (avutometinib) and MEK1/2 inhibitor (trametinib). Cell viability analysis demonstrated increased sensitivity of RMC-7977 resistant cells to RAF inhibitors compared to the parent H358. Combinations of MEK-targeting agents with either RAF inhibitors or RMC-7977 more effectively suppressed ERK phosphorylation in resistant cells compared to RAF inhibitors combinations with RMC-7977. However, combining RAF inhibitors with RMC-7977 or MEK-targeting agents (MS934, NST-628, avutometinib, or trametinib) more potently inhibited cell proliferation in resistant cells compared with combinations of RMC-7977 with MEK-targeting agents. In the context of siRNA-mediated RAF1 knockdown in RMC-7977 resistant cell line, trametinib treatment reduced ERK phosphorylation and inhibited cell proliferation more deeply than RMC-7977. This suggested that RAF1 may have additional signaling mechanisms beyond activation of MEK/ERK. To elucidate the mechanistic basis of LXH-254 activity in RAF1-amplified cells, we performed RNA sequencing and transcriptional analyses in cells treated with LXH-254, which revealed enrichment of G2/M checkpoint, MYC target, mitotic spindle, E2F target, and DNA repair signatures. Consistent with these observations, RAF inhibitors induced G2/M cell cycle arrest and apoptosis in RAF1-amplified cells, and the apoptotic response was enhanced when combined with RMC-7977 or MEK-targeting agents. Resistant cells exhibited increased nuclear RAF1 expression compared with parental H358. Co-immunoprecipitation experiments reveal enhanced interactions between RAF1 and the mitotic kinases PLK1 and AURKA in resistant cells. Our data indicates that RAF1 amplification rewires signaling states by affecting nuclear G2/M signaling networks in addition to the MEK/ERK pathway. More broadly, our results suggest that RAF1 gene amplification associated with RAS inhibitor resistance may produce neomorphic signaling states that affect therapeutic sensitivity. Citation Format: Hitendra S. Solanki, Denis Imbody, ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"44 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358868","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}

{"title":"Abstract IA005: Mutant KRAS-Targeted Vaccines for Cancer Treatment and Interception","authors":"Elizabeth M. Jaffee","doi":"10.1158/1538-7445.rasoncother26-ia005","DOIUrl":"https://doi.org/10.1158/1538-7445.rasoncother26-ia005","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of only 13%. Mutant KRAS (mKRAS) is an oncogenic driver found in >90% of PDACs and the majority of associated precancer lesions, including >90% of PanINs and 80-90% of IPMNs. As a shared neoantigen thought to be the initiating genetic event driving precancer lesions and maintaining the PDAC malignancy phenotype, mKRAS is an attractive target for both precision immunotherapy of established PDAC, and for immune interception strategies in the precancer setting. We previously reported that vaccination against mKRAS can slow the progression of early PanIN lesions to invasive cancer and prolong survival in a KRASG12D-driven mouse model of PDAC. More recently, we reported the safety and induction of mKRAS-specific T cell responses with a first in patients mKRAS synthetic long peptide (SLP) vaccine given with ipilimumab and nivolumab to patients following surgical resection and adjuvant chemotherapy for localized PDAC. Patients demonstrating mKRAS immunity had associated prolonged recurrence-free survival. This SLP vaccine consisting of six 21-amino acid peptides, each carrying one of 6 mutations in the middle of the SLP, is now in testing for interception of PanINs and IPMNs. The results of these studies and future implications will be discussed. Citation Format: Elizabeth M. Jaffee. Mutant KRAS-Targeted Vaccines for Cancer Treatment and Interception [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 IA005.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"28 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147358921","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}

{"title":"METTL3 Methylation Induces Decay of Endogenous Retroelement Transcripts to Promote Tumor Immune Evasion.","authors":"Xiaowei She,Jingqin Lan,Haokun Zhang,Gen Lu,Jialu Xu,Jiakun Zhang,Wenli Zhan,Shengjie Feng,Zejun Rao,Chengxin Yu,Baolin Han,Rui Zhang,Da Song,Yaqi Chen,Guihua Wang,Junbo Hu,Xuelai Luo,Haijie Li","doi":"10.1158/0008-5472.can-25-2893","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2893","url":null,"abstract":"Colorectal cancer (CRC) progression and recurrence persist as major clinical challenges. Emerging evidence underscores that crosstalk between malignant cells and the immunosuppressive microenvironment facilitates tumor relapse, and elucidating the mechanistic details of this crosstalk could help guide development of improved therapies. Here, we identified di-methylation of lysine 513 (K513) on methyltransferase-like 3 (METTL3) as a key modification associated with CRC progression and recurrence. Mechanistically, SETD1A catalyzed METTL3 K513 methylation, enhancing its binding affinity to S-adenosylmethionine (SAM) and augmenting RNA m⁶A deposition. METTL3 methylation suppressed endogenous retroelements expression, leading to impaired type I interferon responses and tumor immune evasion. Fluorouracil induced an E2F4/SETD1A/METTL3 regulatory axis, wherein E2F4 self-regulation activated SETD1A to drive METTL3 methylation. Targeting this axis through pharmacological inhibition of E2F4 or genetic disruption of METTL3 methylation cooperated with immune checkpoint blockade (ICB) to significantly suppress tumor growth. These findings unveil a methylation-dependent regulatory mechanism that reshapes the tumor immune microenvironment, offering a therapeutic strategy for CRC.","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":"147350341","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}

{"title":"PKM2 Lactylation Promotes Colorectal Cancer Vasculogenic Mimicry and Bevacizumab Resistance by Facilitating FOSL1 Super-Enhancer Formation.","authors":"Weihao Li,Jianhong Peng,Jiahua He,Leen Liao,Da Kang,Weili Zhang,Weifeng Wang,Ruowei Wang,Song Wang,Yuanbin Liao,Long Yu,Qingjian Ou,Yujing Fang,Xiaojun Wu,Peirong Ding,Zhizhong Pan,Chi Zhou,Junzhong Lin","doi":"10.1158/0008-5472.can-25-3520","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-3520","url":null,"abstract":"Despite the clinical utility of bevacizumab in advanced colorectal cancer (CRC), resistance remains a major challenge. Here, we unveiled a lactate-mediated mechanism driving vasculogenic mimicry (VM) and bevacizumab resistance through PKM2 lactylation. PKM2 lactylation at K206 by AARS1 promoted PKM2 nuclear translocation and interaction with FOSL1. PKM2 binding facilitated FOSL1-dependent super-enhancer formation and target gene transcription, which contributed to CRC cell VM. Genetic or pharmacological inhibition of PKM2 lactylation disrupted VM and synergized with bevacizumab in patient-derived pre-clinical models, significantly improving therapeutic efficacy. Together, this study reveals lactylation as a metabolic switch linking cancer glycolytic reprogramming to transcriptional rewiring and proposes targeting PKM2 lactylation to enhance the anti-tumor activity of bevacizumab in CRC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"93 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350780","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}