30P Investigation of KRAS G12C inhibitor JAB-21822 as a single agent and in combination with SHP2 inhibitor JAB-3312 in preclinical cancer models

While the currently available KRASG12C-selective inhibitors including Sotorasib have shown promising efficacy, acquired resistance eventually occurred in most cancer patients following treatment. Blocking SHP2, one of critical upstream nodes, represents a rationalized strategy to overcome resistance. We have previously developed JAB-21822, a selective covalent KRASG12C inhibitor and JAB-3312, a selective allosteric SHP2 inhibitor, both of which have entered multiple clinical trials. Cell growth inhibitory effect of JAB-21822 was evaluated in various human cancer cell lines, as well as Ba/F3 cells expressing different KRASG12C mutants with or without secondary point mutations that contribute to KRASG12C inhibitor resistance. Tumor growth inhibitory effect of JAB-21822 was also evaluated in cell line- and patient-derived xenografts. Using similar approaches, the effect of JAB-21822 in combination with JAB-3312 was evaluated in KRASG12C inhibitor-resistant tumor cells and xenograft models. Furthermore, RNA-seq was performed to identify genes with altered expression in KRAS12C inhibitor-resistant NCI-H358 cells compared to their parental counterparts. Expression of selected candidate genes were further confirmed by real-time PCR. As a single agent, JAB-21822 showed early potent antitumor effect both in vitro and in vivo. RNA-seq further identified potential genes involved in KRASG12C inhibitor resistance. Significantly, combination of JAB-21822 with JAB-3312 exerted synergistic effect in the KRASG12C inhibitor-resistant tumor cells and xenograft models tested. JAB-21822 is a promising KRASG12C-targeting drug and, when combined with JAB-3312, can overcome adaptive resistance to KRASG12C inhibition. These preclinical data have provided rationale for our clinical trial featuring the two drugs combination in treating KRASG12C inhibitor-resistant cancer patients.