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  3. Inhibition of γ-secretase/Notch pathway as a potential therapy for reversing cancer drug resistance

Inhibition of γ-secretase/Notch pathway as a potential therapy for reversing cancer drug resistance

  • Biochem Pharmacol. 2023 Dec 20:115991. doi: 10.1016/j.bcp.2023.115991.
Mei Feng 1,  Ramesh Kumar Santhanam 2,  Huan Xing 3,  Mingsheng Zhou 4,  Hui Jia 5
Affiliations

Affiliations

  • 1 Science and Experimental Research Center of Shenyang Medical College, Shenyang 110034, China; Shenyang Key Laboratory of Vascular Biology, Shenyang 110034, China.
  • 2 Faculty of Science and Marine Environment, University Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia.
  • 3 Science and Experimental Research Center of Shenyang Medical College, Shenyang 110034, China.
  • 4 Science and Experimental Research Center of Shenyang Medical College, Shenyang 110034, China; Shenyang Key Laboratory of Vascular Biology, Shenyang 110034, China. Electronic address: zhoums1963@163.com.
  • 5 School of Traditional Chinese Medicine, Shenyang Medical College, Shenyang 110034, China. Electronic address: huijia412413@symc.edu.cn.
PMID: 38135129 DOI: 10.1016/j.bcp.2023.115991
Abstract

The mechanism of tumor drug resistance is complex and may involve stem cell maintenance, epithelial-mesenchymal transition, the activation of survival signaling pathways, transporter protein expression, and tumor microenvironment remodeling, all of which are linked to γ-secretase/Notch signaling. Increasing evidence has shown that the activation of the γ-secretase/Notch pathway is a key driver of Cancer progression and drug resistance development and that γ-secretase inhibitors (GSIs) may be the most promising agents for reversing chemotherapy resistance of tumors by targeting the γ-secretase/Notch pathway. Here, we systematically summarize the roles in supporting γ-secretase/Notch activation-associated transformation of Cancer cells into Cancer Stem Cells, promotion of the EMT process, PI3K/Akt, MEK/ERK and NF-κB activation, enhancement of ABC transporter protein expression, and TME alteration in mediating tumor drug resistance. Subsequently, we analyze the mechanism of GSIs targeting the γ-secretase/Notch pathway to reverse tumor drug resistance and propose the outstanding advantages of GSIs in treating breast Cancer Drug Resistance over other tumors. Finally, we emphasize that the development of GSIs for reversing tumor drug resistance is promising.

Keywords

Cancer stem cells; EMT; TME; Tumor resistance; γ-Secretase inhibitors; γ-Secretase/Notch pathway.

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