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Ref Type Journal Article
PMID (26779812)
Authors Du Y, Yamaguchi H, Wei Y, Hsu JL, Wang HL, Hsu YH, Lin WC, Yu WH, Leonard PG, Lee GR 4th, Chen MK, Nakai K, Hsu MC, Chen CT, Sun Y, Wu Y, Chang WC, Huang WC, Liu CL, Chang YC, Chen CH, Park M, Jones P, Hortobagyi GN, Hung MC
Title Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors.
Journal Vol Issue Date Pages Journal Short Title
Nature medicine 22 2 2016 Feb 194-201 Nat Med
URL
Abstract Text Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients whose tumors show high c-Met expression and who do not respond to PARP inhibition alone.

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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