JAB-3312, a Potent Allosteric SHP2 Inhibitor That Enhances the Efficacy of RTK/RAS/MAPK and PD-1 Blockade Therapies

PURPOSE: Recent advances have seen the development of targeted therapeutics against the receptor tyrosine kinase (RTK)/RAS/MAPK pathway, which, when aberrantly activated, drives the malignant transformation of many cancer indications. However, the efficacy of inhibitors targeting single molecules is dampened by pathway feedback activation and acquired drug resistance. We seek to evaluate the application of JAB-3312 (sitneprotafib), a potent inhibitor of SHP2, in RTK/RAS/MAPK pathway-targeted combination therapies. Furthermore, SHP2 plays a vital role in PD-1-mediated immunosuppression. The rational combination of JAB-3312 with PD-1 blocking therapies is also explored. EXPERIMENTAL DESIGN: Biochemical and cellular assays were applied to evaluate the potency of JAB-3312 in SHP2 inhibition. Tumor cell lines and cell line- and patient-derived xenografts were used to test different combinations of JAB-3312 with KRASG12C, MEK, EGFR, and PD-1 inhibitors. RESULTS: JAB-3312 produced potent in vitro inhibition of SHP2 activity and downstream ERK phosphorylation, with IC50 values of 1.44 nmol/L and 0.68 to 4.84 nmol/L, respectively. When used in combination, JAB-3312 significantly increased the antitumor activity of the KRASG12C inhibitor glecirasib in naïve and resistant models. The combination of JAB-3312 with MEK inhibitors significantly delayed RTK signaling reactivation and enhanced tumor growth inhibition in KRAS-mutated cancer models. The JAB-3312-osimertinib combination exhibited great efficacy in osimertinib-resistant non-small cell lung cancer models. Additionally, JAB-3312 enhanced the efficacy of PD-1 blockade therapies by promoting an antitumor microenvironment. Representative cases of patients who responded to the combination therapies from two ongoing clinical trials (NCT05288205 and NCT04720976) were reported. CONCLUSIONS: JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockade therapies is a promising strategy that warrants further clinical investigation.