2011
DOI: 10.1038/onc.2011.212
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Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer

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Cited by 98 publications
(88 citation statements)
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“…Inhibition of Notch signaling alone has been shown to be not sufficient to inhibit neurosphere recovery and required combinatorial therapy with a chemotherapeutic agent such as temozolomide (48). Recent study showed that GSI MRK-003 treatment irreversibly affected sphere formation in the primary breast tumor cells, but the effect was reversible in the primary normal mammary epithelial cells suggesting differences in the sensitivities of the 2 cell populations (20). On the basis of these observations, it is tempting to speculate that irreversible inhibition of sphere formation caused by mAb 602.101 would be limited to the CSC No.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…Inhibition of Notch signaling alone has been shown to be not sufficient to inhibit neurosphere recovery and required combinatorial therapy with a chemotherapeutic agent such as temozolomide (48). Recent study showed that GSI MRK-003 treatment irreversibly affected sphere formation in the primary breast tumor cells, but the effect was reversible in the primary normal mammary epithelial cells suggesting differences in the sensitivities of the 2 cell populations (20). On the basis of these observations, it is tempting to speculate that irreversible inhibition of sphere formation caused by mAb 602.101 would be limited to the CSC No.…”
Section: Discussionmentioning
confidence: 99%
“…Activation of Notch signaling results in elevated self-renewal, as shown by increased mammosphere formation, whereas inhibition of Notch signaling had the opposite effect (19). Inhibition of Notch signaling also affected the tumorsphere-forming capacity of breast cancer cells (20). Thus, Notch signaling provides a potential therapeutic target for breast cancer treatment.…”
Section: Introductionmentioning
confidence: 99%
“…Furthermore, treatment with the γ-secretase inhibitor MRK-003 could irreversibly inhibit tumor initiating cell proliferation and survival but had reversible effects on normal mammospheres, thus permitting normal stem cell survival. 55 Additional studies have also examined the importance of Notch signaling in the cancer stem cell population. Notch inhibition was also prominent in glioblastoma neurospheres, whose growth was attenuated upon treatment with all-trans retinoic acid, an agent typically used to induce differentiation.…”
Section: Normal and Cancer Stem Cellsmentioning
confidence: 99%
“…γ-Secretase inhibitors (GSIs) (DAPT and MRK-003), which prevent Notch cleavage, genetic silencing of Notch1 and Notch4, as well as blocking Notch1 ligand activation using a monoclonal antibody (14)(15)(16)(17), are all able to reduce mammosphere formation in vitro and number of tumor initiating cells in vivo, supporting the notion that targeting Notch signaling may facilitate durable tumor regression (15,18). It has become apparent from phase I and II clinical trials using GSIs, that these compounds may have a doselimiting toxicity profile, primarily concerning gastrointestinal goblet cell hyperplasia (19)(20)(21).…”
mentioning
confidence: 99%