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Corrigendum: Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors
- Source :
- Nature medicine
- Publication Year :
- 2016
-
Abstract
- Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials1. One PARP inhibitor, olaparib (Lynparzaâ„¢, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with BRCA mutations. BRCA1 and BRCA2 play essential roles in repairing DNA double strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition2,3. Here we show that receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907. Phosphorylation of PARP1 Tyr907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. Combining c-Met and PARP1 inhibitors synergized to suppress growth of breast cancer cells in vitro and xenograft tumor models. Similar synergistic effects were observed in a lung cancer xenograft tumor model. These results suggest that PARP1 pTyr907 abundance may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients bearing tumors with high c-Met expression who do not respond to PARP inhibition alone.
- Subjects :
- Article
Subjects
Details
- ISSN :
- 1546170X
- Volume :
- 22
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Nature medicine
- Accession number :
- edsair.pmid..........e7324d2fbec5ea11ca66424121a6ea6a