Identifying Novel Intensity-Specific Regulators of RAS Signaling

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Abstract The mammalian family of RAS small GTPases, composed of HRAS, NRAS, and KRAS, is mutated to remain in an active, oncogenic state in one fifth of all human cancers. Typically, these mutations occur early, initiating tumorigenesis. Of the three family members, KRAS is mutated most often, suggesting that some feature of this gene renders it more likely to initiate tumorigenesis. To this end, our group linked the high frequency with which KRAS is mutated to a bias of rare codons and resulting poor translation of the encoded mRNA. Mechanistically, the lower levels of KRAS protein and KRAS/MAPK signaling intensity circumvent the growth arrest response of senescence, thereby allowing the induction of tumor initiation. Conversely, poor translation of KRAS mRNA is overcome in later disease stages, promoting tumor progression. Thus, different levels of KRAS/MAPK signaling intensity dictate distinct phenotypic outputs during cancer initiation and progression. Therefore, there must be factors that differentially control Ras signaling intensity, and these factors should be critical during either tumor initiation or tumor progression. Such regulators are of great clinical relevance and could open up the door to a whole new class of regulators of Ras signaling for therapeutic intervention. My long-term goal is to identify and therapeutically target “RAS intensity-specific regulators”. To identify these regulators, our group took advantage of the incredible sensitivity of the Drosophila rough eye phenotype to differential levels of Ras signaling. We employed the novel approach of altering codon usage in the Ras gene of Drosophila to compare high and low Ras signaling. We then exploited these two genetic backgrounds to execute the first-ever in vivo intensity-specific regulator screen and identified fifteen deficiencies. One deficiency was mapped to the Ribosomal protein S21 (Rps21) gene, which acts as a suppressor of Ras signaling. I therefore plan to investigate the underlying mechanism by which Rps21 suppresses Ras signaling (Aim 1). In addition, I aim to identify other novel intensity-specific regulators of Ras signaling in the remaining deficiencies and elucidate their roles in Ras tumorigenesis in the mammalian setting (Aim 2). Completion of these aims will establish new connections between translational control and Ras signaling, reveal new genetic vulnerabilities in RAS-driven cancer, and finally could unearth a pipeline of potential therapeutic targets to explore for cancer therapies.