Canonical and noncanonical NOTCH signaling in the nongenetic resistance of cancer: distinct and concerted control

Abstract

Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies.

Keywords

canonical NOTCH signaling / noncanonical NOTCH signaling / nongenetic resistance of cancer / cancer stem-like cells / epithelial-to-mesenchymal transition / drug-tolerant persisters / NOTCH inhibitors

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Acknowledgements

We would like to thank Dr. Xiaoling Wang, Ms. Hongli Huang, Dr. Xuewei Wu, and Mr. Yihan Chai from the Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, for their reviewing and giving suggestions for this review. This work was supported by the National Natural Science Foundation of China (Nos. 81974455, 8217110405, and 82173351), the National Key Research and Development Program of China (No. 2018YFA0107800), and the Zhejiang University Startup Fund for Dr. Wei Guo. Special thanks also go to the Mu Xian Hua Stem Cells and Cancer Resistance Fund.

Compliance with ethics guidelines

Conflicts of interest Xianzhe Huang, Wenwei Chen, Yanyan Wang, Dmytro Shytikov, Yanwen Wang, Wangyi Zhu, Ruyi Chen, Yuwei He, Yanjia Yang, and Wei Guo declare that they have no conflict of interest.

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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