Abstract B02: A regulatory role for codon bias in KRAS-driven tumor progression and therapeutic resistance

The RAS genes HRAS, NRAS, and KRAS are mutated in a quarter of all human cancers to drive the initiation and maintenance of cancer. While all three genes encode nearly identical proteins, KRAS is highly enriched, compared to the other isoforms, in rare codons. These rare codons impede translation and subsequent protein expression. Despite this, increased KRAS expression and signaling is associated with malignancy and cancer progression, and KRAS mutations have been implicated as drivers of resistance to diverse targeted therapies. Using a pathway-activating genetic screen in a panel of human cancer cell lines, we find that mutant HRAS actually has greater resistance conferring potential than mutant KRAS. This differential resistance is governed by codon bias, suggesting that KRAS-driven resistance is limited by inefficient protein expression. We hypothesized that KRAS-driven cancer progression and primary resistance to a targeted therapeutic, such as an EGFR inhibitor, is dependent upon both the presence of a KRAS mutation as well as the ability of cancer cells to overcome this translational barrier. Indeed, we find that KRAS-mutant cancer cells globally upregulate translation, which results in enhanced expression of mutant KRAS and the formation of a translationally primed state that can be therapeutically exploited using inhibitors of protein translation. Collectively, these findings reveal a critical regulatory role for codon bias in mediating KRAS-driven therapeutic resistance and cancer progression. Ongoing work seeks to more precisely define the mechanisms governing KRAS translation in the setting of cancer and therapeutic resistance to obtain more specific approaches to target these tumors. Citation Format: Erin Kaltenbrun, Moiez Ali, Sarah Jo Stephens, Christopher Counter, Kris Wood. A regulatory role for codon bias in KRAS-driven tumor progression and therapeutic resistance. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B02.