James G. Christensen, Jill Hallin, Lars D Engstrom, Lauren Hargis, Andrew Calinisan, Ruth Aranda, David M Briere, Niranjan Sudhakar, Vickie Bowcut, Brian R Baer, Joshua A Ballard, Michael R Burkard, Jay B Fell, John P Fischer, Guy P Vigers, Jenny Y Xue, Sole Gatto, Julio Fernandez-Banet, Adam Pavlicek, Karen Velastegui, Richard C Chao, Jeremy Barton, Mariaelena Pierobon, Elisa Baldelli, Emmanuel F Patricoin, Douglas P Cassidy, Matthew A Marx, Igor I Rybkin, Melissa L Johnson, Sai-Hong Ignatius Ou, Piro Lito, Kyriakos P. Papadopoulos, Pasi A Janne and Peter Olson
10.1158/2159-8290.CD-19-1167
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%) of KRASG12C-positive cell line- and patient-derived xenograft models from multiple tumor types and objective responses have been observed in KRASG12C-positive lung and colon adenocarcinoma patients. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant non-clinical models identified mechanisms implicated in limiting anti-tumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of RTKs, 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.
