title: 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.
authors.affiliation: Department of Pathology and Obstetrics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: McAuliffe
authors.forename: Stefanie L
authors.initials: SL
authors.lastname: Morgan
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wyant
authors.forename: Lieu T
authors.initials: LT
authors.lastname: Tran
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Muto
authors.forename: Yu Sarah
authors.initials: YS
authors.lastname: Chen
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Chin
authors.forename: Justin C
authors.initials: JC
authors.lastname: Partridge
authors.forename: Barish B
authors.initials: BB
authors.lastname: Poole
authors.forename: Kuang-Hung
authors.initials: KH
authors.lastname: Cheng
authors.forename: John
authors.initials: J
authors.lastname: Daggett
authors.forename: Kristen
authors.initials: K
authors.lastname: Cullen
authors.forename: Emily
authors.initials: E
authors.lastname: Kantoff
authors.forename: Kathleen
authors.initials: K
authors.lastname: Hasselbatt
authors.forename: Julia
authors.initials: J
authors.lastname: Berkowitz
authors.forename: Michael G
authors.initials: MG
authors.lastname: Muto
authors.forename: Ross S
authors.initials: RS
authors.lastname: Berkowitz
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Dinulescu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002453:Cell Cycle; D016923:Cell Death; D002945:Cisplatin / Q000627:therapeutic use*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D002945:Cisplatin