Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling.

PURPOSE SHP2 inhibitors offer an appealing and novel approach to inhibit RTK signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTKi and MAPKi. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor TNO155 to inform their clinical development. EXPERIMENTAL DESIGN The combinations of TNO155 with EGFRi, BRAFi, KRASG12Ci, CDK4/6i and anti-PD-1 antibody were tested in appropriate cancer models in vitro and in vivo, and their effects on downstream signaling were examined. RESULTS In EGFR mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient-derived xenografts, including those with KRAS mutations. Lastly, TNO155 effectively inhibited RAS activation by CSF1R, which is critical for the maturation of immunosuppressive tumor associated macrophages, and showed combination activity with anti-PD-1 antibody. CONCLUSIONS Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.