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Ref Type Journal Article
PMID (40333694)
Authors Kang D, Wang Y, Lin Y, Ma WW, Morgensztern D, Leventakos K, Bi C, Ding Y, Xiong J, Yan M, Sun X, Wang P, Ma C, Wang Y
Title JAB-3312, a Potent Allosteric SHP2 Inhibitor That Enhances the Efficacy of RTK/RAS/MAPK and PD-1 Blockade Therapies.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 31 14 2025 Jul 15 3019-3032 Clin Cancer Res
URL
Abstract Text 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.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.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.JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockade therapies is a promising strategy that warrants further clinical investigation.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 amp FGFR2 amp breast carcinoma sensitive JAB-3312 Preclinical - Cell culture Actionable In a preclinical study, JAB-3312 inhibited viability of an FGFR1 and FGFR2-amplified invasive breast carcinoma cell line in culture (PMID: 40333694). 40333694
NRAS R68T NRAS D92N head and neck cancer sensitive JAB-3312 Preclinical - Cell culture Actionable In a preclinical study, JAB-3312 inhibited viability of a head and neck cancer cell line harboring NRAS D92N and R68T in culture (PMID: 40333694). 40333694
BRAF G466V lung non-small cell carcinoma sensitive JAB-3312 Preclinical - Cell culture Actionable In a preclinical study, JAB-3312 inhibited viability of a non-small cell lung cancer cell line harboring BRAF G466V in culture (PMID: 40333694). 40333694
BRAF G596R colorectal cancer sensitive JAB-3312 Preclinical - Cell culture Actionable In a preclinical study, JAB-3312 inhibited viability of a colorectal cancer cell line harboring BRAF G596R in culture (PMID: 40333694). 40333694
FLT3 exon 14 ins leukemia sensitive JAB-3312 Preclinical - Cell culture Actionable In a preclinical study, JAB-3312 inhibited viability of leukemia cell lines harboring a FLT3-ITD mutation in culture (PMID: 40333694). 40333694