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

Yi Du1, Hirohito Yamaguchi1, Yongkun Wei1

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

Nature Medicine
|January 19, 2016
PubMed

Insights

Poly (ADP-ribose) polymerase (PARP) inhibitors show promise in cancer treatment. New research reveals c-Met phosphorylation of PARP1 can cause resistance to PARP inhibitors, suggesting combination therapy for improved outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Poly (ADP-ribose) polymerase (PARP) inhibitors are emerging cancer therapeutics, with olaparib approved for BRCA-mutated ovarian cancer.
  • BRCA1/2 deficiency sensitizes cancer cells to PARP inhibition due to impaired DNA double-strand break repair.

Purpose of the Study:

  • To investigate the mechanism by which cancer cells develop resistance to PARP inhibitors.
  • To explore the potential of targeting the c-Met/PARP1 pathway for overcoming PARP inhibitor resistance.

Main Methods:

  • Investigated the interaction between c-Met and PARP1 using biochemical assays.
  • Assessed the effect of c-Met phosphorylation on PARP1 activity and PARP inhibitor binding.
  • Evaluated the efficacy of combined c-Met and PARP1 inhibition in preclinical cancer models.

Main Results:

  • The receptor tyrosine kinase c-Met was found to associate with and phosphorylate PARP1 at Tyr907 (PARP1 pTyr907).
  • PARP1 pTyr907 enhances PARP1 enzymatic activity and decreases its binding affinity for PARP inhibitors, leading to resistance.
  • Combination therapy with c-Met and PARP1 inhibitors demonstrated synergistic tumor growth suppression in breast and lung cancer models.

Conclusions:

  • PARP1 phosphorylation by c-Met is a novel mechanism of resistance to PARP inhibitors.
  • PARP1 pTyr907 abundance may serve as a predictive biomarker for PARP inhibitor resistance.
  • Combined inhibition of c-Met and PARP1 offers a potential therapeutic strategy for patients resistant to PARP inhibitors alone, particularly those with high c-Met expression.

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