RRC ID 68965
Author Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, Sudhakar N, Bowcut V, Baer BR, Ballard JA, Burkard MR, Fell JB, Fischer JP, Vigers GP, Xue Y, Gatto S, Fernandez-Banet J, Pavlicek A, Velastagui K, Chao RC, Barton J, Pierobon M, Baldelli E, Patricoin EF 3rd, Cassidy DP, Marx MA, Rybkin II, Johnson ML, Ou SI, Lito P, Papadopoulos KP, Jänne PA, Olson P, Christensen JG.
Title The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients.
Journal Cancer Discov
Abstract Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRASG12C-positive cell line- and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. SIGNIFICANCE: The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRASG12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents.See related commentary by Klempner and Hata, p. 20.This article is highlighted in the In This Issue feature, p. 1.
Volume 10(1)
Pages 54-71
Published 2020-1-1
DOI 10.1158/2159-8290.CD-19-1167
PII 2159-8290.CD-19-1167
PMID 31658955
PMC PMC6954325
MeSH Acetonitriles / therapeutic use* Adenocarcinoma of Lung / drug therapy* Adenocarcinoma of Lung / genetics Adenocarcinoma of Lung / pathology Animals Antineoplastic Agents / therapeutic use* Apoptosis Cell Proliferation Clinical Trials, Phase I as Topic Disease Models, Animal* Female Humans Lung Neoplasms / drug therapy* Lung Neoplasms / genetics Lung Neoplasms / pathology Mice Mice, Inbred BALB C Mice, Inbred NOD Mice, Nude Mice, SCID Middle Aged Mutation* Piperazines / therapeutic use* Prognosis Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors* Proto-Oncogene Proteins p21(ras) / genetics* Pyrimidines Pyrrolidines / therapeutic use* Signal Transduction Tumor Cells, Cultured Xenograft Model Antitumor Assays
IF 29.497
Human and Animal Cells LU99(RCB1900) LU65(RCB1967) IA-LM(RCB0554)