Mutation specific pan-KRAS inhibitor signaling responses and anti-tumor effect

KRAS is one of the most commonly mutated proteins in cancer and efforts to directly inhibit its function have been ongoing for decades. The most successful of these efforts has been the development of covalent allele specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumor growth in patients. Whether inactive state selective inhibition can be employed to therapeutically target non-G12C KRAS mutants remains under investigation. We have recently discovered and characterized a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS, while sparing NRAS and HRAS. Our study suggests that most KRAS oncoproteins cycle between an active and inactive state in cancer cells and the inhibitor can prevent activation of wild-type and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, Q61H, K117N and A146V/T. Based on preliminary results and through comprehensive genetic, biochemical, transcriptomic and proteomic approaches, I will now study the regulation of different KRAS oncoproteins in cancer cells and identify optimal therapeutic applications. In this proposal I will aim to identify mutant specific features (aim 1), regulators (aim 2), and combination therapy (aim 3) throughout KRAS mutant cell lines and mouse models using the pan-KRAS inhibitor (KRASi) described above. The impact of the proposed work here will provide new insight into molecular and biochemical properties of KRAS oncoproteins in cancer. The training component described in the proposed work includes activities to facilitate my transition to an independent principal investigator position. During the K22 phase, I will attend courses, gain hands on experience in order to learn new techniques and attend meetings to expand my network for future collaborations. This award will provide me with the necessary resources and expertise to ensure the successful completion of the training phase of the grant, so that I can transition to a productive career as an independent and well-rounded principal investigator.