Abstract
Abstract Oncogenic KRAS has multiple effects on cellular functions. A relatively poorly understood role of oncogenic KRAS is in regulation of nutrient stress. As a strategy to identify new KRAS-specific tumor vulnerabilities, we sought to explore the role of oncogenic KRAS in mediating the response to nutrient stress. A key observation is that the gene expression signature of oncogenic KRAS is markedly different in standard tissue culture conditions compared to more physiologic levels of glutamine. Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes TCA cycle intermediates and contributes to redox metabolism. We identified oncogenic KRAS as an important regulator of the response to glutamine deprivation in non-small cell lung cancer (NSCLC). A significant fraction of the gene expression signature mediated by KRAS in low glutamine is mediated by activation of ATF4. Activation of the ATF4 stress response pathway is dependent on PI3K and expression of NRF2 downstream of oncogenic KRAS in NSCLC. Through this mechanism, KRAS alters amino acid uptake and metabolism and sustains mTORC1 signaling during nutrient stress. We identified regulation of asparagine synthetase (ASNS) as a key effect of oncogenic KRAS signaling via ATF4 during glutamine deprivation. Preliminary data indicates that simultaneous blockade of PI3K and ASNS may be a useful therapeutic strategy in lung cancer. Our studies underscore an important role for KRAS in metabolism of NSCLC and identify a need for further studies that evaluate KRAS vulnerabilities under conditions of nutrient stress. Citation Format: Alejandro Sweet-Cordero. A novel KRAS specific vulnerability in the nutrient stress response [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA13.
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