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Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance
Moiez Ali1, Erin Kaltenbrun1, Gray R Anderson1
1Department of Pharmacology and Cancer Biology, Duke University, Durham, North California 27710, USA.
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.
Insights
Mutant HRAS, not KRAS, drives resistance in colorectal cancer due to codon bias. Upregulating translation aids KRAS-driven resistance, suggesting translational inhibitors as a therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- KRAS mutations are key drivers of resistance to targeted therapies like EGFR inhibitors in colorectal cancer (CRC).
- HRAS mutations are rare in CRC, but their role in resistance is largely unexplored.
- Understanding resistance mechanisms is crucial for developing effective cancer treatments.
Purpose of the Study:
- To investigate the differential roles of HRAS and KRAS mutations in driving resistance to targeted therapies in colorectal cancer.
- To elucidate the molecular mechanisms underlying HRAS- and KRAS-mediated drug resistance.
- To identify potential therapeutic strategies for overcoming resistance.
Main Methods:
- Utilized genetic screens to identify genes driving resistance.
- Analyzed codon bias and protein expression levels of HRAS and KRAS.
- Assessed the impact of KRAS mutational status and protein expression on cetuximab resistance.
- Investigated the role of translation upregulation in acquired resistance.
- Evaluated the efficacy of translational inhibitors in overcoming resistance.
Main Results:
- Mutant HRAS unexpectedly emerged as a stronger driver of resistance than mutant KRAS in colorectal cancer.
- Higher protein expression of HRAS, attributed to codon bias, explains its potent resistance role compared to KRAS.
- Primary resistance to cetuximab correlated with both KRAS mutation status and protein expression levels.
- Acquired resistance was linked to specific KRAS mutations (e.g., KRASQ61) effective even at low protein expression.
- Cancer cells upregulated translation to support KRASG12-driven acquired resistance, leading to hypersensitivity to translational inhibitors.
Conclusions:
- Codon bias significantly influences the expression and function of RAS proteins, impacting drug resistance in colorectal cancer.
- Targeting translation represents a promising therapeutic approach to overcome KRAS-driven resistance in colorectal cancer.
- These findings offer new insights into the complex mechanisms of cancer drug resistance and suggest novel therapeutic avenues.
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