Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance

Moiez Ali, Erin Kaltenbrun, Grace R. Anderson, Sarah Jo Stephens, Sabrina Arena, Alberto Bardelli, Christopher M. Counter, Kris C. Wood

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

KRAS mutations drive resistance to targeted therapies, including EGFR inhibitors in colorectal cancer (CRC). Through genetic screens, we unexpectedly find that mutant HRAS, which is rarely found in CRC, is a stronger driver of resistance than mutant KRAS. This difference is ascribed to common codon bias in HRAS, which leads to much higher protein expression, and implies that the inherent poor expression of KRAS due to rare codons must be surmounted during drug resistance. In agreement, we demonstrate that primary resistance to cetuximab is dependent upon both KRAS mutational status and protein expression level, and acquired resistance is often associated with KRAS Q61 mutations that function even when protein expression is low. Finally, cancer cells upregulate translation to facilitate KRAS G12 -driven acquired resistance, resulting in hypersensitivity to translational inhibitors. These findings demonstrate that codon bias plays a critical role in KRAS-driven resistance and provide a rationale for targeting translation to overcome resistance.

Original languageEnglish
Article number15617
JournalNature Communications
Volume8
DOIs
Publication statusPublished - Jun 8 2017

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Codon
Colorectal Neoplasms
Mutation
Proteins
Drug Resistance
cancer
Hypersensitivity
Up-Regulation
Therapeutics
mutations
proteins
Cells
inhibitors
Pharmaceutical Preparations
Neoplasms
therapy
drugs
Cetuximab

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance. / Ali, Moiez; Kaltenbrun, Erin; Anderson, Grace R.; Stephens, Sarah Jo; Arena, Sabrina; Bardelli, Alberto; Counter, Christopher M.; Wood, Kris C.

In: Nature Communications, Vol. 8, 15617, 08.06.2017.

Research output: Contribution to journalArticle

Ali, Moiez ; Kaltenbrun, Erin ; Anderson, Grace R. ; Stephens, Sarah Jo ; Arena, Sabrina ; Bardelli, Alberto ; Counter, Christopher M. ; Wood, Kris C. / Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance. In: Nature Communications. 2017 ; Vol. 8.
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