Chemotherapy reduces PARP1 in cancers of the ovary: Implications for future clinical trials involving PARP inhibitors

Maud Marques, Marie Claude Beauchamp, Hubert Fleury, Ido Laskov, Sun Qiang, Manuela Pelmus, Diane Provencher, Anne Marie Mes-Masson, Walter H. Gotlieb, Michael Witcher

Research output: Contribution to journalArticlepeer-review

Abstract

Background: PARP inhibitors have shown promising clinical results in cancer patients carrying BRCA1/2 mutations. Their clinical efficacy could logically be influenced by PARP1 protein levels in patient tumors. Methods: We screened three cohorts of patients with ovarian cancer, totaling 313 samples, and evaluated PARP1 protein expression by immunohistochemistry with further validation by western blotting. Results: We observed that up to 60% of tumors showed little PARP1 protein expression. In serous ovarian tumors, comparing intratumoral PARP1 expression between chemo-naïve and post-chemotherapy patients revealed a decrease in intratumoral PARP1 following chemotherapy in all three cohorts (immunohistochemistry: p < 0.001, n = 239; western blot: p = 0.012, n = 74). The findings were further confirmed in a selection of matched samples from the same patients before and after chemotherapy. Conclusion: Our data suggest that patients should be screened for PARP1 expression prior to therapy with PARP inhibitors. Further, the observed reduction of intratumoral PARP1 post-chemotherapy suggests that treating chemo-naïve patients with PARP inhibitors prior to the administration of chemotherapy, or concurrently, might increase the responsiveness to PARP1 inhibition. Thus, a change in the timing of PARP inhibitor administration may be warranted for future clinical trials.

Original languageEnglish
Article number217
JournalBMC Medicine
Volume13
Issue number1
DOIs
StatePublished - 9 Sep 2015
Externally publishedYes

Keywords

  • Chemotherapy
  • ovarian cancer
  • PARP inhibitors
  • PARP1

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