Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance.
Journal Article (Journal Article)
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 KRASQ61 mutations that function even when protein expression is low. Finally, cancer cells upregulate translation to facilitate KRASG12-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.
Full Text
Duke Authors
Cited Authors
- Ali, M; Kaltenbrun, E; Anderson, GR; Stephens, SJ; Arena, S; Bardelli, A; Counter, CM; Wood, KC
Published Date
- June 8, 2017
Published In
Volume / Issue
- 8 /
Start / End Page
- 15617 -
PubMed ID
- 28593995
Pubmed Central ID
- PMC5472712
Electronic International Standard Serial Number (EISSN)
- 2041-1723
Digital Object Identifier (DOI)
- 10.1038/ncomms15617
Language
- eng
Conference Location
- England