Targeting apoptosis in cancer therapy

By B. Carneiro, W. El-Deiry. Nature Reviews Clinical Oncology, 2020

1,802 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/8aaa1d82b86f3c6dedf17066cc1a964fe9c404b4

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In Molecular Biology

1. Yan Yu
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3. Yang Zhou
4. Todd R. Golub
5. Xuepeng Wang

Citations in the corpus

• PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway? (2022, background): “Overall, the mechanisms of apoptosis evasion and carcinogenesis are mediated by the imbalance of Bcl-2 family proteins, reduced caspases expression, disrupted death receptor signaling pathway, p53 defects/mutations, and overexpression of inhibitor of apoptosis proteins (IAPs) such as BIRC1 (NAIP), B”
• Regulated cell death (RCD) in cancer: key pathways and targeted therapies (2022, neutral): “Inhibition or resistance of cell death often leads to the occurrence of tumors.(46,47) Therefore, the regulation of the apoptosis signaling pathway is one of the crucial methods to improve cancer treatment.”
• The role of BCL-2 family proteins in regulating apoptosis and cancer therapy (2022, background): “The mechanism of action of the targeted therapy is that drug molecules cause loss of protein function by occupying the binding pocket or active site of the target protein (4).”
• Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “This pathway is believed to function as a natural barrier against malignancy, but the primary hallmark of cancer cells and the emergence of chemotherapy resistance during cancer therapy are limiting or causing cells to resist apoptosis [20, 21].”
• Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “Nevertheless, therapeutic agents targeting apoptosis regulators such as apoptosis-related caspases or B-cell lymphoma-2 (BCL-2) family proteins have poor effects in antitumor therapy.(5) On the contrary, non-apoptotic RCD affects the development of cancer and its response to therapy.”
• Copper induces cell death by targeting lipoylated TCA cycle proteins (2022, background): “Cell death involves signaling cascades and molecularly-defined effector mechanisms (20) involving proteins and lipids such as those characteristic of apoptosis (21), necroptosis (22), pyroptosis (23) and ferroptosis (24), which is a recently discovered iron-dependent cell death pathway.”