1. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.
- Author
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Wasko UN, Jiang J, Dalton TC, Curiel-Garcia A, Edwards AC, Wang Y, Lee B, Orlen M, Tian S, Stalnecker CA, Drizyte-Miller K, Menard M, Dilly J, Sastra SA, Palermo CF, Hasselluhn MC, Decker-Farrell AR, Chang S, Jiang L, Wei X, Yang YC, Helland C, Courtney H, Gindin Y, Muonio K, Zhao R, Kemp SB, Clendenin C, Sor R, Vostrejs WP, Hibshman PS, Amparo AM, Hennessey C, Rees MG, Ronan MM, Roth JA, Brodbeck J, Tomassoni L, Bakir B, Socci ND, Herring LE, Barker NK, Wang J, Cleary JM, Wolpin BM, Chabot JA, Kluger MD, Manji GA, Tsai KY, Sekulic M, Lagana SM, Califano A, Quintana E, Wang Z, Smith JAM, Holderfield M, Wildes D, Lowe SW, Badgley MA, Aguirre AJ, Vonderheide RH, Stanger BZ, Baslan T, Der CJ, Singh M, and Olive KP
- Subjects
- Animals, Female, Humans, Mice, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Disease Models, Animal, DNA Copy Number Variations, Drug Resistance, Neoplasm drug effects, Genes, myc, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local genetics, Treatment Outcome, Xenograft Model Antitumor Assays, Mutation, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Guanosine Triphosphate metabolism, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors
- 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 variants3 . More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4 . 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., (© 2024. The Author(s).)- Published
- 2024
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