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Ref Type Journal Article
PMID (30949414)
Authors Han Y, Chen MK, Wang HL, Hsu JL, Li CW, Chu YY, Liu CX, Nie L, Chan LC, Yam C, Wang SC, He GJ, Hortobagyi GN, Tan XD, Hung MC
Title Synergism of PARP inhibitor fluzoparib (HS10160) and MET inhibitor HS10241 in breast and ovarian cancer cells.
Journal American journal of cancer research
Vol 9
Issue 3
Date 2019
URL
Abstract Text Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are promising targeted therapeutics for breast and ovarian cancers bearing a germline BRCA1/2 mutation (BRCAm), and several have already received regulatory approval in the United States. In patients with a BRCAm cancer, PARPi can increase the burden of unrepaired DNA double-strand breaks by blocking PARP activity and trapping PARP1 onto damaged DNA. Resistance to PARP inhibitors can block the formation of DNA double-strand breaks through BRCA-related DNA repair pathway. MET is a hyper-activated receptor tyrosine kinase expressed in multiple cancer types and the activation contributes to resistance to DNA damage-inducing therapeutic drugs. Our previous study showed that MET inhibition by pan-kinase inhibitors has synergism with PARPi in suppressing growth of breast cancer in vitro and in xenograft tumor models. In this study, we validated the inhibitory effect of novel inhibitors, HS10241 (selective MET inhibitor) and HS10160 (PARPi), to their target respectively in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC) cells. We further demonstrated that these two inhibitors function synergistically in eliminating TNBC and HGSOC cells; combining with HS10241 increased DNA double-strand breaks induced by HS10160 in cancer cells; and PARP1 tyrosine (Y)-907 phosphorylation (PARP1 p-Y907) can be an effective biomarker as an indicator of MET-mediated PARPi in HGSOC. Our results suggest that the combination of HS10241 and HS10160 may benefit patients bearing tumors overexpressing MET as well as those resistant to single-agent PARPi treatment.

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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
HS10241 HS-10241 MET Inhibitor 51 HS10241 is a MET inhibitor that blocks the activation of Met, which potentially inhibits downstream signaling and induces cytotoxicity (PMID: 30949414).
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
Unknown unknown triple-receptor negative breast cancer not applicable Fluzoparib Preclinical - Cell culture Actionable In a preclinical study, Fluzoparib inhibited DNA-damage-induced PARylation in breast cancer cell lines in culture, however, the cells demonstrated resistance to Fluzoparib treatment (PMID: 30949414). 30949414
Unknown unknown ovarian cancer not applicable Fluzoparib Preclinical - Cell culture Actionable In a preclinical study, Fluzoparib inhibited DNA-damage-induced PARylation in high-grade serous ovarian cancer cell lines in culture, however, the cells demonstrated resistance to Fluzoparib treatment (PMID: 30949414). 30949414