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

Moiez Ali, Erin Kaltenbrun, Gray R. Anderson, Sarah Jo Stephens, Sabrina Arena, Alberto Bardelli, Christopher M. Counter () and Kris C. Wood ()
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Moiez Ali: Duke University
Erin Kaltenbrun: Duke University
Gray R. Anderson: Duke University
Sarah Jo Stephens: Duke University
Sabrina Arena: University of Torino
Alberto Bardelli: University of Torino
Christopher M. Counter: Duke University
Kris C. Wood: Duke University

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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 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.

Date: 2017
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DOI: 10.1038/ncomms15617

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