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Cancer Discov. 2019 Jun;9(6):738-755. doi: 10.1158/2159-8290.CD-18-1220. Epub 2019 Apr 5.

Tissue-Specific Oncogenic Activity of KRASA146T.

Author information

1
Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
2
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
3
Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
4
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
5
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts.
6
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
7
Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
8
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
9
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
10
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts.
11
Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
12
Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. khaigis@bidmc.harvard.edu Kenneth.Westover@UTSouthwestern.edu.
13
Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts. khaigis@bidmc.harvard.edu Kenneth.Westover@UTSouthwestern.edu.
14
Harvard Digestive Disease Center, Harvard Medical School, Boston, Massachusetts.
#
Contributed equally

Abstract

KRAS is the most frequently mutated oncogene. The incidence of specific KRAS alleles varies between cancers from different sites, but it is unclear whether allelic selection results from biological selection for specific mutant KRAS proteins. We used a cross-disciplinary approach to compare KRASG12D, a common mutant form, and KRASA146T, a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that KRASA146T exhibits a marked extension of switch 1 away from the protein body and nucleotide binding site, which activates KRAS by promoting a high rate of intrinsic and guanine nucleotide exchange factor-induced nucleotide exchange. Using mice genetically engineered to express either allele, we found that KRASG12D and KRASA146T exhibit distinct tissue-specific effects on homeostasis that mirror mutational frequencies in human cancers. These tissue-specific phenotypes result from allele-specific signaling properties, demonstrating that context-dependent variations in signaling downstream of different KRAS mutants drive the KRAS mutational pattern seen in cancer. SIGNIFICANCE: Although epidemiologic and clinical studies have suggested allele-specific behaviors for KRAS, experimental evidence for allele-specific biological properties is limited. We combined structural biology, mass spectrometry, and mouse modeling to demonstrate that the selection for specific KRAS mutants in human cancers from different tissues is due to their distinct signaling properties.See related commentary by Hobbs and Der, p. 696.This article is highlighted in the In This Issue feature, p. 681.

Comment in

PMID:
30952657
PMCID:
PMC6548671
[Available on 2020-06-01]
DOI:
10.1158/2159-8290.CD-18-1220

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