SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling.

KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site-specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.
Competing Interests: Disclosures: C.J.R. Foster reported grants from the National Institutes of Health during the conduct of the study. K-K. Wong reported "other" from G1 Therapeutics, Zentalis Therapeutics, and Epiphanes Therapeutics outside the submitted work, and has consulting/sponsored research agreements with the following: AstraZeneca, Janssen, Pfizer, Novartis, Merck, Ono, and Array (consulting and sponsored research); MedImmune, Mirati (which developed MRTX 1257), Takeda, TargImmune, and BMS (sponsored research only). B.G. Neel reported "other" from Navire Pharma, Northern Biologics, Ltd, Arvinas, Inc, Regeneron, Amgen, Inc, Mirati Therapeutics, Gilead Therapeutics, and Moderna outside the submitted work. In addition, B.G. Neel has a patent to PCT 63031457 pending. No other disclosures were reported.
(© 2020 Fedele et al.)