Design and Development of a Small Molecule-controlled Activator of RAS

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DESCRIPTION (provided by applicant): Over forty years since the declaration of the "War on Cancer," malignancy remains a scourge on human health. Not long after that declaration, the three genes that encode RAS proteins were discovered to be among the most prominent molecular players in cancer. RAS functions as a molecular switch, existing in either an "on" or "off" state. When on, RAS instigates a wide variety of signaling cascades that control survival, proliferation, and many other cellular processes. In healthy cells, RAS integrates signals coming from outside the cell to determine cellular response. In approximately 20% of human tumors, however, mutations in RAS cause it to become "stuck" in the on position. This constitutively active RAS leads to aberrant downstream signaling and malignant transformation of the cell. Together, the three RAS isoforms constitute the most frequently mutated oncogene in human cancers. Notably, RAS mutations are especially prevalent in some of the most intractable malignancies, e.g. pancreatic, lung, and colon cancers. Yet, after nearly four decades of research, no targeted therapy for mutant RAS tumors has been discovered. In large part, this is a result of RAS being "undruggable": it is notoriously difficult to directly inhibit with a drug-lie small molecule. The obstinance of RAS means that it's signaling must be dissected with uncompromising depth to identify alternate strategies for targeting these tumors. Despite extensive study, it is still unclear how such a simple on/off switch can govern so many cellular responses of such complexity, or why in some circumstances, activated RAS causes a cell to proliferate, but in others, it causes the cell to senesce. To address these long-standing questions in RAS and cancer biology, we have engineered a chemically-induced activator of RAS (CIAR). With this construct, we are able to activate RAS signaling with a small molecule in a rapid and dose-dependent fashion. This control will permit previously inaccessible studies of the effects of the magnitude and duration of RAS signaling on the phosphoproteome, transcriptome, and malignant phenotype. Furthermore, by localizing CIAR to different subcellular compartments, we will address how spatiotemporal compartmentalization of RAS signaling and effects signaling and trancriptional networks as well as phenotype. The information gleaned from these studies may then guide the identification of novel strategies for targeting tumors bearing RAS mutations.