Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer
Year: 2024
Type: article
Abstract: 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.
Source: Nature
Authors: Urszula N. Wasko, Jingjing Jiang, Tanner C. Dalton, Alvaro Curiel-Garcia, A. Cole Edwards, Yingyun Wang, Bianca Lee, Margo Orlen, Sha Tian, Clint A. Stalnecker, Kristina Drizyte-Miller, Marie Menard, Julien Dilly, Stephen A. Sastra, Carmine F. Palermo, Marie C. Hasselluhn, Amanda R. Decker-Farrell, Stephanie Chang, Lingyan Jiang, Xing Wei, Yu C. Yang, Ciara Helland, Haley Courtney, Yevgeniy Gindin, Karl Muonio, Ruiping Zhao, Samantha B. Kemp, Cynthia Clendenin, Rina Sor, William P. Vostrejs, Priya S. Hibshman, Amber M. Amparo, Connor Hennessey, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Jens Brodbeck, Lorenzo Tomassoni, Basil Bakir, Nicholas D. Socci, Laura E. Herring, Natalie K. Barker, Junning Wang, James M. Cleary, Brian M. Wolpin, John A. Chabot, Michael D. Kluger, Gulam A. Manji, Kenneth Y. Tsai, Miroslav Sekulic, Stephen M. Lagana, Andrea Califano, Elsa Quintana, Zhengping Wang, Jacqueline A. M. Smith, Matthew Holderfield, David Wildes, Scott W. Lowe, Michael A. Badgley, Andrew J. Aguirre, Robert H. Vonderheide, Ben Z. Stanger, Timour Baslan, Channing J. Der, Mallika Singh, Kenneth P. Olive
Institutions: Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center, Revolution Medicines (United States), University of North Carolina at Chapel Hill, University of Pennsylvania, Memorial Sloan Kettering Cancer Center, UNC Lineberger Comprehensive Cancer Center, Harvard University, Dana-Farber Cancer Institute, Abramson Cancer Center, Broad Institute, Columbia University, Moffitt Cancer Center, Johns Hopkins University, Johns Hopkins Medicine, Chan Zuckerberg Biohub New York, Howard Hughes Medical Institute, Brigham and Women's Hospital, Parker Institute for Cancer Immunotherapy
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,290
Funders: U.S. Department of Defense, American Cancer Society, Pancreatic Cancer Action Network, Lustgarten Foundation, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: G1042255685, G1047483779, G1111229574, G1133076894, G1820872495, G2296513394, Storage System for High Performance Computing, G2684890037, High Performance Computing Cluster for Biomedical Research, G2765941256, Molecular Determinants and Therapeutic Consequences of Immune Heterogeneity in Cancer, G3873960122, Targeting undruggable RAS for cancer treatment, G4424250656, G4516325861, High-performance compute cluster for biomedical computing, G4934063291, G5351521234, G744782498, Cancer Center Support Grant, Elucidation and targeting of paracrine cascades in PDAC, Elucidating and Targeting tumor dependencies and drug resistance determinants at the single cell level, Mechanisms of response and resistance to KRAS inhibition in pancreatic cancer, Cancer Center Support Grant, Cancer Center Support Grant, The Columbia University Digestive and Liver Disease Research Center
OpenAlex ID: W4394580205