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

Background

While the currently available KRAS^G12C-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 KRAS^G12C inhibitor and JAB-3312, a selective allosteric SHP2 inhibitor, both of which have entered multiple clinical trials.

Methods

Cell growth inhibitory effect of JAB-21822 was evaluated in various human cancer cell lines, as well as Ba/F3 cells expressing different KRAS^G12C mutants with or without secondary point mutations that contribute to KRAS^G12C 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 KRAS^G12C inhibitor-resistant tumor cells and xenograft models. Furthermore, RNA-seq was performed to identify genes with altered expression in KRAS^12C inhibitor-resistant NCI-H358 cells compared to their parental counterparts. Expression of selected candidate genes were further confirmed by real-time PCR.

Results

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 KRAS^G12C inhibitor resistance. Significantly, combination of JAB-21822 with JAB-3312 exerted synergistic effect in the KRAS^G12C inhibitor-resistant tumor cells and xenograft models tested.

Conclusions

JAB-21822 is a promising KRAS^G12C-targeting drug and, when combined with JAB-3312, can overcome adaptive resistance to KRAS^G12C inhibition. These preclinical data have provided rationale for our clinical trial featuring the two drugs combination in treating KRAS^G12C inhibitor-resistant cancer patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Jacobio Pharmaceuticals Co., Ltd.

Funding

AbbVie.

Disclosure

P. Wang, Q. Zheng, D. Kang, X. Sun, S. Zhu, Y. Wang, W. Long, Y. Lin : Financial interests, Personal, Full or part-time Employment: Jacobio Pharmaceuticals Co.