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

• Published in: Nature communications Vol. 8; no. 1; p. 15617
• Main Authors: Ali, Moiez, Kaltenbrun, Erin, Anderson, Gray R., Stephens, Sarah Jo, Arena, Sabrina, Bardelli, Alberto, Counter, Christopher M., Wood, Kris C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.06.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 38/47; 631/67/1059/2326; 631/67/395; 631/67/68; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents, Immunological - pharmacology; Bias; Cancer; Cell Line, Tumor; Cell Proliferation; Cetuximab - pharmacology; Codon - genetics; Codon bias; Codons; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Drug resistance; Drug Resistance, Neoplasm - genetics; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; Genetic screening; Humanities and Social Sciences; Humans; Hypersensitivity; Inhibitors; K-Ras protein; Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; multidisciplinary; Mutants; Mutation; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Panitumumab; Protein expression; Proteins; Proto-Oncogene Proteins p21(ras) - genetics; RNA Interference; RNA, Small Interfering - genetics; Science; Translation; Italy
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15617

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. KRAS mutations drive resistance to diverse targeted therapies. In this study, the authors show that the rare codons of KRAS , yielding low oncogene expression, can be overcome to drive resistance to anti-EGFR therapy in CRC through upregulation of global translation or through selection of more potent KRAS Q61 mutations.