Pub Date : 2024-08-23DOI: 10.1038/s43018-024-00814-0
Ulrike Rauh, Guo Wei, Michael Serrano-Wu, Georgios Kosmidis, Stefan Kaulfuss, Franziska Siegel, Kai Thede, James McFarland, Christopher T Lemke, Nicolas Werbeck, Katrin Nowak-Reppel, Sabine Pilari, Stephan Menz, Matthias Ocker, Weiqun Zhang, Kyle Davis, Guillaume Poncet-Montange, Jennifer Roth, Douglas Daniels, Virendar K Kaushik, Brian Hubbard, Karl Ziegelbauer, Todd R Golub
The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials.
{"title":"BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models.","authors":"Ulrike Rauh, Guo Wei, Michael Serrano-Wu, Georgios Kosmidis, Stefan Kaulfuss, Franziska Siegel, Kai Thede, James McFarland, Christopher T Lemke, Nicolas Werbeck, Katrin Nowak-Reppel, Sabine Pilari, Stephan Menz, Matthias Ocker, Weiqun Zhang, Kyle Davis, Guillaume Poncet-Montange, Jennifer Roth, Douglas Daniels, Virendar K Kaushik, Brian Hubbard, Karl Ziegelbauer, Todd R Golub","doi":"10.1038/s43018-024-00814-0","DOIUrl":"10.1038/s43018-024-00814-0","url":null,"abstract":"<p><p>The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046913","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 : 2024-08-16DOI: 10.1038/s43018-024-00806-0
Meghri Katerji, Maxine R. Rubin, John Brognard
Precision medicine holds immense promise for treating individuals with cancer. A new study unveils MTX-531 — a drug that can inhibit two signaling proteins, EGFR and PI3K — which was developed through innovative computational drug design and offers new hope for more-effective and better-tolerated cancer treatments.
{"title":"Dual inhibition of EGFR and PI3K with a single drug","authors":"Meghri Katerji, Maxine R. Rubin, John Brognard","doi":"10.1038/s43018-024-00806-0","DOIUrl":"10.1038/s43018-024-00806-0","url":null,"abstract":"Precision medicine holds immense promise for treating individuals with cancer. A new study unveils MTX-531 — a drug that can inhibit two signaling proteins, EGFR and PI3K — which was developed through innovative computational drug design and offers new hope for more-effective and better-tolerated cancer treatments.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996152","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 : 2024-08-16DOI: 10.1038/s43018-024-00808-y
Anders Hofer
Resistance of cancers to immune checkpoint blockades is frequently observed. Pancreatic cancer cells are now shown to create a tumor microenvironment that protects them from immunotherapy by overexpression of cytidine deaminase. This leads to increased production of uridine diphosphate that attracts immunosuppressive macrophages.
{"title":"How tumors hijack macrophages for immune evasion","authors":"Anders Hofer","doi":"10.1038/s43018-024-00808-y","DOIUrl":"10.1038/s43018-024-00808-y","url":null,"abstract":"Resistance of cancers to immune checkpoint blockades is frequently observed. Pancreatic cancer cells are now shown to create a tumor microenvironment that protects them from immunotherapy by overexpression of cytidine deaminase. This leads to increased production of uridine diphosphate that attracts immunosuppressive macrophages.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996153","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}
The tumor microenvironment (TME) considerably influences colorectal cancer (CRC) progression, therapeutic response and clinical outcome, but studies of interindividual heterogeneities of the TME in CRC are lacking. Here, by integrating human colorectal single-cell transcriptomic data from approximately 200 donors, we comprehensively characterized transcriptional remodeling in the TME compared to noncancer tissues and identified a rare tumor-specific subset of endothelial cells with T cell recruitment potential. The large sample size enabled us to stratify patients based on their TME heterogeneity, revealing divergent TME subtypes in which cancer cells exploit different immune evasion mechanisms. Additionally, by associating single-cell transcriptional profiling with risk genes identified by genome-wide association studies, we determined that stromal cells are major effector cell types in CRC genetic susceptibility. In summary, our results provide valuable insights into CRC pathogenesis and might help with the development of personalized immune therapies.
{"title":"Integrative single-cell analysis of human colorectal cancer reveals patient stratification with distinct immune evasion mechanisms.","authors":"Xiaojing Chu, Xiangjie Li, Yu Zhang, Guohui Dang, Yuhui Miao, Wenbin Xu, Jinyu Wang, Zemin Zhang, Sijin Cheng","doi":"10.1038/s43018-024-00807-z","DOIUrl":"10.1038/s43018-024-00807-z","url":null,"abstract":"<p><p>The tumor microenvironment (TME) considerably influences colorectal cancer (CRC) progression, therapeutic response and clinical outcome, but studies of interindividual heterogeneities of the TME in CRC are lacking. Here, by integrating human colorectal single-cell transcriptomic data from approximately 200 donors, we comprehensively characterized transcriptional remodeling in the TME compared to noncancer tissues and identified a rare tumor-specific subset of endothelial cells with T cell recruitment potential. The large sample size enabled us to stratify patients based on their TME heterogeneity, revealing divergent TME subtypes in which cancer cells exploit different immune evasion mechanisms. Additionally, by associating single-cell transcriptional profiling with risk genes identified by genome-wide association studies, we determined that stromal cells are major effector cell types in CRC genetic susceptibility. In summary, our results provide valuable insights into CRC pathogenesis and might help with the development of personalized immune therapies.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988356","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 : 2024-08-12DOI: 10.1038/s43018-024-00801-5
Combining SOS1 inhibitors with KRAS inhibitors improved the depth and durability of response in lung and colorectal cancer models. Restoration of response was observed in preclinical models rendered resistant to KRAS inhibitors. These results highlight the potential of SOS1 inhibitors to broaden the response to KRAS inhibitors in the clinic.
{"title":"SOS1 inhibitor combinations overcome KRAS inhibitor resistance","authors":"","doi":"10.1038/s43018-024-00801-5","DOIUrl":"https://doi.org/10.1038/s43018-024-00801-5","url":null,"abstract":"Combining SOS1 inhibitors with KRAS inhibitors improved the depth and durability of response in lung and colorectal cancer models. Restoration of response was observed in preclinical models rendered resistant to KRAS inhibitors. These results highlight the potential of SOS1 inhibitors to broaden the response to KRAS inhibitors in the clinic.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933568","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 : 2024-08-12DOI: 10.1038/s43018-024-00802-4
Erik N. Bergstrom, Ludmil B. Alexandrov
Recent advancements in targeted immune checkpoint blockade (ICB) therapy have reshaped cancer treatment paradigms. However, many patients do not respond, highlighting the need for robust biomarkers. A study now introduces an approach using multi-omics data and machine learning to improve patient selection for ICB therapy, offering more effective treatment.
{"title":"Enhanced precision in immunotherapy","authors":"Erik N. Bergstrom, Ludmil B. Alexandrov","doi":"10.1038/s43018-024-00802-4","DOIUrl":"10.1038/s43018-024-00802-4","url":null,"abstract":"Recent advancements in targeted immune checkpoint blockade (ICB) therapy have reshaped cancer treatment paradigms. However, many patients do not respond, highlighting the need for robust biomarkers. A study now introduces an approach using multi-omics data and machine learning to improve patient selection for ICB therapy, offering more effective treatment.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933565","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 : 2024-08-05DOI: 10.1038/s43018-024-00800-6
Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann
Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.
{"title":"Co-targeting SOS1 enhances the antitumor effects of KRAS<sup>G12C</sup> inhibitors by addressing intrinsic and acquired resistance.","authors":"Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann","doi":"10.1038/s43018-024-00800-6","DOIUrl":"10.1038/s43018-024-00800-6","url":null,"abstract":"<p><p>Combination approaches are needed to strengthen and extend the clinical response to KRAS<sup>G12C</sup> inhibitors (KRAS<sup>G12C</sup>i). Here, we assessed the antitumor responses of KRAS<sup>G12C</sup> mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRAS<sup>G12C</sup> inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRAS<sup>G12C</sup>i seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRAS<sup>G12C</sup>i treatment. These results suggest KRAS<sup>G12C</sup> plus SOS1i to be a promising strategy for treating both KRAS<sup>G12C</sup>i naive and relapsed KRAS<sup>G12C</sup>-mutant tumors.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893812","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 : 2024-07-26DOI: 10.1038/s43018-024-00798-x
Marcel Arias-Badia, Ryan Chang, Lawrence Fong
While the effector cells that mediate anti-tumor immunity have historically been attributed to αβ T cells and natural killer cells, γδ T cells are now being recognized as a complementary mechanism mediating tumor rejection. γδ T cells possess a host of functions ranging from antigen presentation to regulatory function and, importantly, have critical roles in eliciting anti-tumor responses where other immune effectors may be rendered ineffective. Recent discoveries have elucidated how these differing functions are mediated by γδ T cells with specific T cell receptors and spatial distribution. Their relative resistance to mechanisms of dysfunction like T cell exhaustion has spurred the development of therapeutic approaches exploiting γδ T cells, and an improved understanding of these cells should enable more effective immunotherapies. Fong and colleagues provide a Review on γδ T cells as mediators of anti-tumor immunity, discuss their role in the tumor microenvironment and reflect on therapeutic approaches to exploit γδ T cells.
介导抗肿瘤免疫的效应细胞历来被认为是 αβ T 细胞和自然杀伤细胞，而 γδ T 细胞现在被认为是介导肿瘤排斥反应的补充机制。γδT细胞具有从抗原递呈到调节功能的一系列功能，重要的是，在其他免疫效应因子可能失效的情况下，γδT细胞在激发抗肿瘤反应方面发挥着关键作用。最新发现阐明了具有特定 T 细胞受体和空间分布的 γδ T 细胞是如何介导这些不同功能的。γδT细胞对T细胞衰竭等功能障碍机制具有相对抵抗力，这推动了利用γδT细胞的治疗方法的发展。
{"title":"γδ T cells as critical anti-tumor immune effectors","authors":"Marcel Arias-Badia, Ryan Chang, Lawrence Fong","doi":"10.1038/s43018-024-00798-x","DOIUrl":"10.1038/s43018-024-00798-x","url":null,"abstract":"While the effector cells that mediate anti-tumor immunity have historically been attributed to αβ T cells and natural killer cells, γδ T cells are now being recognized as a complementary mechanism mediating tumor rejection. γδ T cells possess a host of functions ranging from antigen presentation to regulatory function and, importantly, have critical roles in eliciting anti-tumor responses where other immune effectors may be rendered ineffective. Recent discoveries have elucidated how these differing functions are mediated by γδ T cells with specific T cell receptors and spatial distribution. Their relative resistance to mechanisms of dysfunction like T cell exhaustion has spurred the development of therapeutic approaches exploiting γδ T cells, and an improved understanding of these cells should enable more effective immunotherapies. Fong and colleagues provide a Review on γδ T cells as mediators of anti-tumor immunity, discuss their role in the tumor microenvironment and reflect on therapeutic approaches to exploit γδ T cells.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766741","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}
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