Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer

• 成果类型: Article
• 署名作者: Wasko, Urszula N.; Jiang, Jingjing; Dalton, Tanner C.; Curiel-Garcia, Alvaro; Edwards, A. Cole; Wang, Yingyun; Lee, Bianca; Orlen, Margo; Tian, Sha; Stalnecker, Clint A.; Drizyte-Miller, Kristina; Menard, Marie; Dilly, Julien; Sastra, Stephen A.; Palermo, Carmine F.; Hasselluhn, Marie C.; Decker-Farrell, Amanda R.; Chang, Stephanie; Jiang, Lingyan; Wei, Xing; Yang, Yu C.; Helland, Ciara; Courtney, Haley; Gindin, Yevgeniy; Muonio, Karl; Zhao, Ruiping; Kemp, Samantha B.; Clendenin, Cynthia; Sor, Rina; Vostrejs, William P.; Hibshman, Priya S.; Amparo, Amber M.; Hennessey, Connor; Rees, Matthew G.; Ronan, Melissa M.; Roth, Jennifer A.; Brodbeck, Jens; Tomassoni, Lorenzo; Bakir, Basil; Socci, Nicholas D.; Herring, Laura E.; Barker, Natalie K.; Wang, Junning; Cleary, James M.; Wolpin, Brian M.; Chabot, John A.; Kluger, Michael D.; Manji, Gulam A.; Tsai, Kenneth Y.; Sekulic, Miroslav; Lagana, Stephen M.; Califano, Andrea; Quintana, Elsa; Wang, Zhengping; Smith, Jacqueline A. M.; Holderfield, Matthew; Wildes, David; Lowe, Scott W.; Badgley, Michael A.; Aguirre, Andrew J.; Vonderheide, Robert H.; Stanger, Ben Z.; Baslan, Timour; Der, Channing J.; Singh, Mallika; Olive, Kenneth P.
• 署名单位: NewYork-Presbyterian Hospital; Columbia University; Columbia University; NewYork-Presbyterian Hospital; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of Pennsylvania; Memorial Sloan Kettering Cancer Center; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; University of Pennsylvania; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Columbia University; NewYork-Presbyterian Hospital; Memorial Sloan Kettering Cancer Center; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; NewYork-Presbyterian Hospital; Columbia University; H Lee Moffitt Cancer Center & Research Institute; H Lee Moffitt Cancer Center & Research Institute; NewYork-Presbyterian Hospital; Columbia University; Johns Hopkins University; Columbia University; NewYork-Presbyterian Hospital; Columbia University; Columbia University; NewYork-Presbyterian Hospital; Chan Zuckerberg Initiative (CZI); Howard Hughes Medical Institute; Memorial Sloan Kettering Cancer Center; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; University of Pennsylvania
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6504
• DOI: 10.1038/s41586-024-07379-z
• 发表日期: 2024-05-23
• 关键词: oncogenic kras; mouse; kras(g12d); efficacy; package; models; gene

摘要

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations 1,2 . RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants 3 . More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS 4 . Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance. RMC-7977, a multi-selective RAS(ON) inhibitor, exhibits potent tumour-selective activity in multiple pre-clinical models of pancreatic ductal adenocarcinoma through a combination of pharmacology and oncogene dependence.