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Cell. 2018 Feb 8;172(4):857-868.e15. doi: 10.1016/j.cell.2017.12.020. Epub 2018 Jan 11.

KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: chiara_ambrogio@dfci.harvard.edu.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Departments of Biochemistry and Radiation Oncology, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
School of Life Science and Technology, Tongji University, 200092 Shanghai, China.
5
Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Molecular Biotechnology and Health Science, University of Torino, 10126, Italy.
6
University of Bordeaux, INSERM U1218, ACTION Laboratory, IECB, F-33600 Pessac, France.
7
Departments of Biochemistry and Radiation Oncology, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: kenneth.westover@utsouthwestern.edu.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: pasi_janne@dfci.harvard.edu.

Abstract

The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.

KEYWORDS:

KRAS oncogene; MAPK pathway; MEK inhibitors; allelic imbalance; dimerization; drug resistance; lung adenocarcinoma; wild-type allele

PMID:
29336889
DOI:
10.1016/j.cell.2017.12.020
[Indexed for MEDLINE]
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