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 resi...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.展开更多
基金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)the Zhejiang University Startup Fund for Dr.Wei Guo.Special thanks also go to the Mu Xian Hua Stem Cells and Cancer Resistance Fund.
文摘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.
