An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants. Academic Article uri icon

Overview

abstract

  • KRAS is the most frequently mutated oncogene in cancer, yet there is little understanding of how specific KRAS amino acid changes affect tumor initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R), and colon (KRASG13D) cancers. Induction of each allele in either the murine colon or pancreas revealed striking quantitative and qualitative differences between KRAS mutants in driving the early stages of transformation. Furthermore, using pancreatic organoid models, we show that KRASG13D mutants are sensitive to EGFR inhibition, whereas KRASG12C-mutant organoids are selectively responsive to covalent G12C inhibitors only when EGFR is suppressed. Together, these new mouse strains provide an ideal platform for investigating KRAS biology in vivo and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers. SIGNIFICANCE: KRAS is the most frequently mutated oncogene. Here, we describe new preclinical models that mimic tissue-selective KRAS mutations and show that each mutation has distinct cellular consequences in vivo and carries differential sensitivity to targeted therapeutic agents.See related commentary by Kostyrko and Sweet-Cordero, p. 1626.This article is highlighted in the In This Issue feature, p. 1611.

publication date

  • August 12, 2020

Research

keywords

  • Alleles
  • Oncogenes
  • Proto-Oncogene Proteins p21(ras)

Identity

PubMed Central ID

  • PMC7642097

Scopus Document Identifier

  • 85095416834

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-20-0442

PubMed ID

  • 32792368

Additional Document Info

volume

  • 10

issue

  • 11