Therapeutic resistance: Opportunities created by adaptive responses to cancer targeted therapy

2022-05-09 0 By

23 March 2022 Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer (Nat Rev Cancer, IF: 60.716) Labrie Marilyne,Brugge Joan S,Mills Gordon B et al. Therapy Resistance:opportunities created by adaptive responses to targeted therapies in cancer.[J] .Nat Rev Cancer, 2022, undefined: undefined. Normal cells explore multiple states to survive stresses encountered during development and self-renewal as well as environmental stresses such as starvation, DNA damage, toxins or infection. Cancer cells co-opt normal stress mitigation pathways to survive stresses that accompany tumour initiation, progression, metastasis and immune evasion. Cancer therapies accentuate cancer cell stresses and invoke rapid non-genomic stress mitigation processes that maintain cell viability and thus represent key targetable resistance mechanisms. In this Review, we describe mechanisms by which tumour ecosystems, including cancer cells, immune cells and stroma, adapt to therapeutic stresses and describe three different approaches to exploit stress mitigation processes: (1) interdict stress mitigation to induce cell death; (2) increase stress to induce cellular catastrophe; and (3) exploit emergent vulnerabilities in cancer cells and cells of the tumour microenvironment. We review challenges associated with tumour heterogeneity, prioritizing actionable adaptive responses for optimal therapeutic outcomes, and development of an integrative framework to identify and target vulnerabilities that arise from adaptive responses and engagement of stress mitigation pathways. Finally, we discuss the need to monitor adaptive responses across multiple scales and translation of combination therapies designed to take advantage of adaptive responses and stress mitigation pathways to the clinic. Normal cells explore multiple states in order to survive the stresses encountered during development and self-renewal, as well as environmental stresses such as starvation, DNA damage, toxins or infections.Cancer cells use normal stress relief pathways to survive the stress that accompanies tumor initiation, progression, metastasis, and immune evasion.Cancer therapy emphasizes the stress of cancer cells and invokes rapid non-genomic stress relief processes to keep cells alive, thus representing key targeted resistance mechanisms.In this review, we describe the mechanisms by which tumor ecosystems, including cancer cells, immune cells, and stroma, adapt to therapeutic stress, and describe three different approaches to develop stress relief processes :(1) blocking stress relief induces cell death;(2) Increased stress induced cell mutation;(3) Exploit vulnerabilities that arise in cancer cells and tumor microenvironment cells.We review the challenges associated with tumor heterogeneity, prioritize actionable adaptive responses for optimal treatment outcomes, and develop a comprehensive framework to identify and target vulnerabilities from adaptive responses and stress relief pathways.Finally, we discuss the need to monitor adaptive responses across multiple scales and to translate combination therapies aimed at exploiting adaptive response and stress relief pathways into clinical treatment.Declaration: The copyright of this article belongs to the original author, if there is a source error or infringement of your legitimate rights and interests, you can contact us through the mailbox, we will promptly deal with.Email address: jpbl@jp.jiupainews.com