Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy

Shannon M. McAuliffe, Stefanie L. Morgan, Gregory A. Wyant, Lieu T. Tran, Katherine W. Muto, Yu Sarah Chen, Kenneth T. Chin, Justin C. Partridge, Barish B. Poole, Kuang Hung Cheng, John Daggett, Kristen Cullen, Emily Kantoff, Kathleen Hasselbatt, Julia Berkowitz, Michael G. Muto, Ross S. Berkowitz, Jon C. Aster, Ursula A. Matulonis, Daniela M. Dinulescu

Research output: Contribution to journalArticlepeer-review

Abstract

Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G2/Mcell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant.

Original languageEnglish (US)
Pages (from-to)E2939-E2948
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number43
DOIs
StatePublished - Oct 23 2012
Externally publishedYes

Keywords

  • Isobologram and combination index analysis
  • Notch3 expression patterns
  • Platinum-induced DNA damage response
  • Synergistic cytotoxic effects for GSI/cisplatin combination therapy
  • Tumor models

ASJC Scopus subject areas

  • General

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