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

Nature Medicine volume 22, pages 194–201 (2016)Cite this article

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A Corrigendum to this article was published on 06 October 2016

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Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials1. 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 inhibition2,3. 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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Figure 1: ROS induce the association of c-Met and PARP1.
Figure 2: c-Met regulates resistance to PARP inhibitors.
Figure 3: c-Met mediates PARP1 functions through phosphorylation of PARP1 at Y907.
Figure 4: Clinical relevance and potential therapeutic strategy targeting PARP1 and c-Met in TNBC.

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  • 25 August 2016

    In the version of this article initially published, the concentrations of H2O2 were incorrectly labeled as micromolar (μM) instead of millimolar (mM) in the legends of Figures 1h, 3c–f and Supplementary Figures 3, 8f–h, 10g,j and 12c,d. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This study was funded in part by the following: the US National Institutes of Health grants (nos. CA109311 (M.-C. Hung) and CA099031 (M.-C. Hung), and a Cancer Center Support Grant CA16672); the Susan G. Komen Foundation (SAC100016 (M.-C. Hung)); the Breast Cancer Research Foundation; the Patel Memorial Breast Cancer Endowment Fund; The University of Texas MD Anderson–China Medical University and Hospital Sister Institution Fund; the Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE; MOST 104-2911-I-002-302 (M.-C. Hung)); the Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW104-TDU-B-212-124-002 (M.-C. Hung)); the Center for Biological Pathways at The University of Texas MD Anderson Cancer Center; and the Ting Tsung and Wei Fong Chao Research Fund. We also thank S. Patterson of the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for her editorial assistance.

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Yi Du, Hirohito Yamaguchi, Yongkun Wei, Jennifer L Hsu, Yi-Hsin Hsu, Wan-Chi Lin, Wen-Hsuan Yu, Mei-Kuang Chen, Katsuya Nakai, Ming-Chuan Hsu, Chun-Te Chen, Ye Sun & Mien-Chie Hung

  2. Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan

    Hung-Ling Wang, Wei-Chao Chang & Mien-Chie Hung

  3. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA

    Wen-Hsuan Yu, Mei-Kuang Chen & Mien-Chie Hung

  4. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Paul G Leonard & Gilbert R Lee IV

  5. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Paul G Leonard, Gilbert R Lee IV & Philip Jones

  6. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Yun Wu

  7. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Wei-Chao Chang & Chung-Hsuan Chen

  8. Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan

    Wen-Chien Huang, Chien-Liang Liu & Yuan-Ching Chang

  9. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    Morag Park

  10. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Gabriel N Hortobagyi

  11. Department of Biotechnology, Asia University, Taichung, Taiwan

    Mien-Chie Hung

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Contributions

Y.D. designed and performed the experiments, analyzed data and wrote the manuscript; H.Y., Y.W., Y.-H.H., W.-C.L., W.-H.Y., P.G.L., G.R.L., W.-C.C., C.-H.C. and M.-K.C. performed experiments and analyzed data; H.-L.W. generated the antibody; M.-C. Hsu, C.-T.C., K.N. and Y.S. performed experiments; Y.W., W-.C.H., C.-L.L. and Y.-C.C. provided patient tissue samples; H.Y. and J.L.H. provided scientific input and wrote the manuscript; M.P. provided transgenic mouse cell lines. G.N.H. provided scientific and clinical input. P.J. provided scientific input. M.-C. Hung supervised the entire project, designed the experiments, analyzed data and wrote the manuscript.

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Correspondence to Mien-Chie Hung.

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Du, Y., Yamaguchi, H., Wei, Y. et al. Blocking c-Met–mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors. Nat Med 22, 194–201 (2016). https://doi.org/10.1038/nm.4032

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