Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer

被引:154
|
作者
Labrie, Marilyne [1 ,2 ,3 ]
Brugge, Joan S. [4 ,5 ]
Mills, Gordon B. [1 ]
Zervantonakis, Ioannis K. [6 ,7 ]
机构
[1] Oregon Hlth & Sci Univ, Div Ontol Sci, Knight Canc Inst, Portland, OR 97201 USA
[2] Univ Sherbrooke, Dept Immunol & Cell Biol, Sherbrooke, PQ, Canada
[3] Univ Sherbrooke, Dept Obstet & Gynecol, Sherbrooke, PQ, Canada
[4] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA
[5] Harvard Med Sch, Ludwig Canc Ctr, Boston, MA 02115 USA
[6] Univ Pittsburgh, UPMC Hillman Canc Ctr, Pittsburgh, PA 15260 USA
[7] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15260 USA
基金
美国国家卫生研究院;
关键词
ENDOPLASMIC-RETICULUM STRESS; DRUG-RESISTANCE; HOMOLOGOUS RECOMBINATION; DNA-DAMAGE; OXIDATIVE-METABOLISM; REPLICATION STRESS; PARP INHIBITOR; BREAST-CANCER; UP-REGULATION; CELLS;
D O I
10.1038/s41568-022-00454-5
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. This Review discusses mechanisms by which tumour ecosystems adapt to therapeutic stresses and how these could be exploited, as well as challenges associated with tumour heterogeneity. It provides an integrative framework to identify and target vulnerabilities that arise from adaptive responses to overcome cancer therapy resistance.
引用
收藏
页码:323 / 339
页数:17
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