Yinuo “Cathy” Meng
Rac1 as a Therapeutic Target to Synergize with KRAS-targeted Therapies
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is mostly driven by KRAS mutations. While KRAS inhibitors have been developed, resistance is common, highlighting a need to identify novel therapeutics. In our preliminary study, we have identified RAC1 as a critical node for PDAC tumor, with its depletion leading to the strongest growth attenuation relative to other effectors. This finding was validated in patient PDAC organoids and was enhanced in classical subtype tumors. Herein, we hypothesize RAC1 is most essential for PDAC maintenance and represents a tractable target to overcome resistance to KRAS inhibition. We will (1) evaluate the efficacy of dual RAC1/KRAS inhibition in PDAC across different KRAS mutations and molecular subtypes in mouse and human systems; and (2) dissect cell-intrinsic mechanisms by which RAC1 regulates PDAC progression. Together, we expect our findings will validate RAC1 targeting to couple with enhance emergent RAS therapies in pursuit of durable clinical responses.
Receiving this fellowship is exceptionally meaningful to me because it affirms the scientific significance of my research and my long-term commitment to advancing cancer therapeutics. It recognizes the significance of my research not only in generating mechanistic insight, but also in translating discovery into clinical benefit.
