Signal Transduction to P70 S6 Kinase 1 - Project Summary. (30 lines) Cancer is the 2nd leading cause of death in the US. The advent of new treatments such as immunotherapy and targeted therapies have revolutionized the fight against cancer, and when combined with surgery or chemo- therapy, often result in positive therapeutic responses. Eventually, however, most tumor cells gain the ability to resist current therapies, making it critical that we continue to define cancer causing and driving processes to increase the available arsenal of anti-cancer drugs. Given the role of metabolism and metabolic environments in cancer progression, understanding these aspects of cancer progression also has the potential to reveal new classes of cancer drugs that take advantage of cancer-associated signaling and metabolic vulnerabilities. mTOR complex 1 (mTORC1), is a protein kinase complex that senses various environmental cues and coordinates anabolic and catabolic processes to regulate cellular homeostasis. mTORC1 becomes activated when amino acids, lipids, energy sources, oxygen and growth factor levels are sufficient. Different cancer cell-associated mutations provide tumor cells with the ability to optimize usage of these regulatory components or find ways to overcome deficiencies in these mTORC1 regulators, including nutrients. Additionally, once activated it is still a mystery how mTORC1 regulates and coordinates the many processes required to promote cell growth, proliferation, migration, and survival. To better understand mTORC1 signaling, we have combined our mTORC1 phospho-proteome, proteome, interactome, metabolome and gene expression data sets, to support new discoveries. In this proposal we have outlined several goals based on these data, our recently published work and the 35 years experience of my lab, that support our long-term goals of defining mTORC1-S6K1 regulation and signaling, and for revealing new information to support efforts to kill cancer cells with activated mTORC1 signaling. Our discoveries and experience are now driving us to; (i) determine how nuclear accumulation of GSK3, upon suppression of mTORC1 signaling, regulates chromatin remodeling and DNA damage repair, nuclear events linked to biological processes altered in cancer cells, (ii) characterize a novel S6K1 effector kinase, SRPK2, and its role in mRNA biogenesis of interferon-stimulated genes and its role in therapy resistance and (iii) define a new link between essential dietary ω-6 and ω-3 fatty acids and mTORC1 activation, highlighting a potential dietary intervention as part of a treatment program for mTORC1-driven cancers . In conclusion, there’s a critical need for a greater understanding of the molecular basis of mTORC1 regulation and signaling, as well as its links to processes associated with cell growth, metabolism, survival and drug resistance. Our expectations are that successful completion of the proposed work will impact cancer biology/physiology and therapy through the identification of new therapeutic targets and biomarkers that can lead to the improve detection and elimination of cancer cells with unregulated mTORC1 signaling, estimated to occur in 70-80% of all human cancers.
