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Cancer Discov. 2019 Oct 28. pii: CD-19-1167. doi: 10.1158/2159-8290.CD-19-1167. [Epub ahead of print]

The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients.

Author information

1
Research, Mirati Therapeutics (United States).
2
Mirati Therapeutics (United States).
3
Research, Mirati Therapeutics.
4
Research - Biology, Mirati Therapeutics (United States).
5
Array BioPharma.
6
Biology, Loxo Oncology.
7
Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center.
8
Monoceros Biosystems LLC.
9
Bioinformatics, Monoceros Biosystems LLC.
10
Center for Applied Proteomics and Molecular Medicine, George Mason University.
11
Center for Applied Protomics and Molecular Medicine, George Mason University.
12
George Mason University.
13
Department of Medical Oncology, Dana-Farber Cancer Institute.
14
Henry Ford Cancer Institute, Henry Ford Health System.
15
Sarah Cannon Research Institute, Tennessee Oncology.
16
Chao Family Comprehensive Cancer Center, University of California, Irvine.
17
Human Oncology and Pathogenesis Program, MSKCC.
18
Hematology/Oncology, START.
19
Medical Oncology, Dana-Farber Cancer Institute.
20
Oncology Research Unit, Pfizer Global Research and Development.
21
Research, Mirati Therapeutics (United States) christensenj@mirati.com.

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%) 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.

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