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

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, G 2 /M cell-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.

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

“…In addition, the deregulation of Notch signalling pathway genes is also involved in the development of platinum resistance and recurrence of EOC 22. Therefore, we hypothesize that genetic variants in Notch signalling pathway genes contribute to death risk of EOC.…”

A Phase I, Dose-Finding Study in Patients with Advanced Solid Malignancies of the Oral γ-Secretase Inhibitor PF-03084014

“…Inhibition of g-secretase represents an attractive therapeutic target expected to result in inhibition of the aberrant NOTCH signaling noted in several cancer types and, consequently, of the associated downstream tumorrelated processes (10)(11)(12)(13). g-Secretase inhibitors were also developed for the treatment of Alzheimer disease, although results from randomized trials did not show benefit (14,15).…”

Regulated Proteolysis of NOTCH2 and NOTCH3 Receptors by ADAM10 and Presenilins

“…Genome sequencing has identified mutations in NOTCH2 and NOTCH3 in carcinomas of the ovary and in squamous head-and-neck and lung cancers, although the consequence of many of these mutations on NOTCH activity is not known (27). In solid breast tumors, expression of NOTCH2 is associated with a better overall survival and with differentiated tumors (28), whereas expression and amplification of NOTCH3 are prognostic for outcome in ovarian cancer and associated with resistance to alkylating chemotherapeutics (29).…”