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

Publication ,  Journal Article
Ali, M; Kaltenbrun, E; Anderson, GR; Stephens, SJ; Arena, S; Bardelli, A; Counter, CM; Wood, KC
Published in: Nat Commun
June 8, 2017

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

June 8, 2017

Volume

8

Start / End Page

15617

Location

England

Related Subject Headings

  • RNA, Small Interfering
  • RNA Interference
  • Proto-Oncogene Proteins p21(ras)
  • Panitumumab
  • Pancreatic Neoplasms
  • Lung Neoplasms
  • Humans
  • ErbB Receptors
  • Drug Resistance, Neoplasm
  • Colorectal Neoplasms
 

Citation

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Ali, M., Kaltenbrun, E., Anderson, G. R., Stephens, S. J., Arena, S., Bardelli, A., … Wood, K. C. (2017). Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance. Nat Commun, 8, 15617. https://doi.org/10.1038/ncomms15617
Ali, Moiez, Erin Kaltenbrun, Gray R. Anderson, Sarah Jo Stephens, Sabrina Arena, Alberto Bardelli, Christopher M. Counter, and Kris C. Wood. “Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance.Nat Commun 8 (June 8, 2017): 15617. https://doi.org/10.1038/ncomms15617.
Ali M, Kaltenbrun E, Anderson GR, Stephens SJ, Arena S, Bardelli A, et al. Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance. Nat Commun. 2017 Jun 8;8:15617.
Ali, Moiez, et al. “Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance.Nat Commun, vol. 8, June 2017, p. 15617. Pubmed, doi:10.1038/ncomms15617.
Ali M, Kaltenbrun E, Anderson GR, Stephens SJ, Arena S, Bardelli A, Counter CM, Wood KC. Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance. Nat Commun. 2017 Jun 8;8:15617.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

June 8, 2017

Volume

8

Start / End Page

15617

Location

England

Related Subject Headings

  • RNA, Small Interfering
  • RNA Interference
  • Proto-Oncogene Proteins p21(ras)
  • Panitumumab
  • Pancreatic Neoplasms
  • Lung Neoplasms
  • Humans
  • ErbB Receptors
  • Drug Resistance, Neoplasm
  • Colorectal Neoplasms