Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors

Nat Med. 2016 Feb;22(2):194-201. doi: 10.1038/nm.4032. Epub 2016 Jan 18.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Benzimidazoles / pharmacology
  • Breast Neoplasms*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Crizotinib
  • Humans
  • In Vitro Techniques
  • Indoles / pharmacology
  • Lung Neoplasms*
  • MCF-7 Cells
  • Mice
  • Neoplasm Transplantation
  • Phosphorylation / drug effects
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerases / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Quinolines / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Anilides
  • Benzimidazoles
  • GSK 1363089
  • Indoles
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Quinolines
  • veliparib
  • Crizotinib
  • rucaparib
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Proto-Oncogene Proteins c-met
  • olaparib