TY - JOUR
T1 - Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy
AU - McAuliffe, Shannon M.
AU - Morgan, Stefanie L.
AU - Wyant, Gregory A.
AU - Tran, Lieu T.
AU - Muto, Katherine W.
AU - Chen, Yu Sarah
AU - Chin, Kenneth T.
AU - Partridge, Justin C.
AU - Poole, Barish B.
AU - Cheng, Kuang Hung
AU - Daggett, John
AU - Cullen, Kristen
AU - Kantoff, Emily
AU - Hasselbatt, Kathleen
AU - Berkowitz, Julia
AU - Muto, Michael G.
AU - Berkowitz, Ross S.
AU - Aster, Jon C.
AU - Matulonis, Ursula A.
AU - Dinulescu, Daniela M.
PY - 2012/10/23
Y1 - 2012/10/23
N2 - 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.
AB - 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.
KW - Isobologram and combination index analysis
KW - Notch3 expression patterns
KW - Platinum-induced DNA damage response
KW - Synergistic cytotoxic effects for GSI/cisplatin combination therapy
KW - Tumor models
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U2 - 10.1073/pnas.1206400109
DO - 10.1073/pnas.1206400109
M3 - Article
C2 - 23019585
AN - SCOPUS:84867919330
SN - 0027-8424
VL - 109
SP - E2939-E2948
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 43
ER -