Targeting apoptosis in cancer therapy

Abstract

For over three decades, a mainstay and goal of clinical oncology has been the development of therapies promoting the effective elimination of cancer cells by apoptosis. This programmed cell death process is mediated by several signalling pathways (referred to as intrinsic and extrinsic) triggered by multiple factors, including cellular stress, DNA damage and immune surveillance. The interaction of apoptosis pathways with other signalling mechanisms can also affect cell death. The clinical translation of effective pro-apoptotic agents involves drug discovery studies (addressing the bioavailability, stability, tumour penetration, toxicity profile in non-malignant tissues, drug interactions and off-target effects) as well as an understanding of tumour biology (including heterogeneity and evolution of resistant clones). While tumour cell death can result in response to therapy, the selection, growth and dissemination of resistant cells can ultimately be fatal. In this Review, we present the main apoptosis pathways and other signalling pathways that interact with them, and discuss actionable molecular targets, therapeutic agents in clinical translation and known mechanisms of resistance to these agents. The authors of this Review present the main pathways that regulate apoptosis as well as other signalling pathways that interact with them, highlighting actionable molecular targets for anticancer therapy. They also provide an overview of therapeutic agents exploiting apoptosis currently in clinical translation and known mechanisms of resistance to these agents. Apoptosis can be induced in cancer cells through intrinsic and extrinsic pathways, which converge on the regulation of caspase-dependent proteolysis of thousands of cellular proteins, membrane blebbing and endonucleolytic cleavage of chromosomal DNA. A limited number of FDA-approved anticancer agents directly target apoptotic pathways; these small molecules are designed to inhibit anti-apoptotic BCL-2 family members. Other promising therapeutic strategies for activating apoptosis in cancer cells include agents that trigger the extrinsic apoptosis pathway, those that target tumour suppressor pathways or the tumour microenvironment, and combination drug therapies. The antitumour efficacy of several FDA-approved agents targeting cell survival and proliferation pathways in cancer cells is also dependent on their effects on apoptosis signalling pathways. Both cell-mediated immunotherapy and immune-checkpoint inhibition induce apoptosis in cancer cells through the extrinsic pathway; the possibility of potentiating this effect using combination regimens (involving targeted therapies, cytotoxic agents or radiotherapy) is currently under investigation.