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Cancer Discov. 2020 Jan;10(1):54-71. doi: 10.1158/2159-8290.CD-19-1167. Epub 2019 Oct 28.

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

Author information

1
Mirati Therapeutics, Inc., San Diego, California.
2
Array BioPharma Inc., Boulder, Colorado.
3
Memorial Sloan Kettering Cancer Center, New York, New York.
4
Monoceros Biosystems LLC, San Diego, California.
5
George Mason University, Manassas, Virginia.
6
Dana-Farber Cancer Institute, Boston, Massachusetts.
7
Henry Ford Medical Center, Detroit, Michigan.
8
Sarah Cannon Research Institute Tennessee Oncology, Nashville, Tennessee.
9
University of California, Irvine, Chao Family Comprehensive Cancer Center, Orange, California.
10
START Center for Cancer Care, San Antonio, Texas.
11
Mirati Therapeutics, Inc., San Diego, California. 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%) 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.

PMID:
31658955
PMCID:
PMC6954325
[Available on 2020-07-01]
DOI:
10.1158/2159-8290.CD-19-1167

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