SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling

Abstract

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.

Mechanisms of Resistance to KRASG12C Inhibitors

“…Indeed, recently updated phase 1 results confirm that sotorasib and adagrasib are well tolerated in patients, with 11.6% of patients receiving sotorasib experiencing grade 3/4 treatment-related adverse effects [ 35 ]. Several possible inhibitory partners have been identified, including SHP2, receptor tyrosine kinases, PI3K and PD-1/L1 [ 27 , 56 , 65 ]. However, there remains a lack of consensus on which of these targets should be prioritised.…”

“…Either inhibitor alone had minimal effects on murine PDAC and NSCLC models, whereas G12C/SHP2 co-inhibition conferred extended survival in all models with no evidence of toxicity. SHP2 co-inhibition also appears to lead to a more favourable immune microenvironment, and sensitised tumours to PD-1 inhibition [ 65 ]. In agreement with these findings, the SHP2 inhibitor TNO155 has been shown to overcome feedback reactivation of RTK signalling induced by G12C inhibition and was found to act synergistically with the G12C inhibitor Cpd 12a to inhibit proliferation in KRAS G12C cell lines.…”

Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC

“…"Driver" mutations (e.g., amplified or mutant RTKs, mutant KRAS) significantly-and differentially-also have tumor cell-intrinsic andextrinsic effects and evoke distinct cellular and humoral responses in different tissues (3). Consequently, SHP2is have important, potentially driver-specific, effects on the tumor microenvironment (TME), including potentially complex effects on anti-tumor immunity (2,(4)(5)(6).…”

“…As the response to targeted therapies in patients almost certainly reflects the composite of direct anti-tumor actions and effects on the TME, CDXs, PDXs, and SQ syngeneic models could provide incomplete or even misleading information about SHP2i action. For example, we found that SHP2i, alone or in combination with KRAS-G12C inhibitor (G12Ci), increased intratumor T cells in KRAS G12C -driven non-small cell lung cancer (NSCLC) and pancreas ductal adenocarcinoma (PDAC) (4). However, the degree of T cell function is still unknown.…”

“…However, the degree of T cell function is still unknown. Moreover, combination with anti-PD1 treatment only resulted in minimal improvement in efficacy (4), urging for a more efficacious, rational combination strategy that enhance immune-modulatory effects of SHP2is.…”