title: Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors.
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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yongkun
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Hung-Ling
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Wan-Chi
authors.initials: WC
authors.lastname: Lin
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
authors.forename: Wen-Hsuan
authors.initials: WH
authors.lastname: Yu
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Leonard
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
authors.forename: Mei-Kuang
authors.initials: MK
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nakai
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ming-Chuan
authors.initials: MC
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Chien-Liang
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Yuan-Ching
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chung-Hsuan
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.|Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D000077547:Crizotinib; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms; D061986:MCF-7 Cells; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D001562:Benzimidazoles; C544831:GSK 1363089; D007211:Indoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011804:Quinolines; C521013:veliparib; D000077547:Crizotinib; C531549:rucaparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019859:Proto-Oncogene Proteins c-met; C531550:olaparib