The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs.
Sarah T DiepstratenMary Ann AndersonPeter E CzabotarGuillaume L LesseneAndreas StrasserGemma L KellyPublished in: Nature reviews. Cancer (2021)
Apoptosis is a form of programmed cell death that is regulated by the balance between prosurvival and proapoptotic BCL-2 protein family members. Evasion of apoptosis is a hallmark of cancer that arises when this balance is tipped in favour of survival. One form of anticancer therapeutic, termed 'BH3-mimetic drugs', has been developed to directly activate the apoptosis machinery in malignant cells. These drugs bind to and inhibit specific prosurvival BCL-2 family proteins, thereby mimicking their interaction with the BH3 domains of proapoptotic BCL-2 family proteins. The BCL-2-specific inhibitor venetoclax is approved by the US Food and Drug Administration and many regulatory authorities worldwide for the treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia. BH3-mimetic drugs targeting other BCL-2 prosurvival proteins have been tested in preclinical models of cancer, and drugs targeting MCL-1 or BCL-XL have advanced into phase I clinical trials for certain cancers. As with all therapeutics, efficacy and tolerability need to be carefully balanced to achieve a therapeutic window whereby there is significant anticancer activity with an acceptable safety profile. In this Review, we outline the current state of BH3-mimetic drugs targeting various prosurvival BCL-2 family proteins and discuss emerging data regarding primary and acquired resistance to these agents and approaches that may overcome this. We highlight issues that need to be addressed to further advance the clinical application of BH3-mimetic drugs, both alone and in combination with additional anticancer agents (for example, standard chemotherapeutic drugs or inhibitors of oncogenic kinases), for improved responses in patients with cancer.
Keyphrases
- cell cycle arrest
- cancer therapy
- oxidative stress
- clinical trial
- endoplasmic reticulum stress
- cell death
- drug induced
- induced apoptosis
- squamous cell carcinoma
- stem cells
- liver failure
- dendritic cells
- papillary thyroid
- acute myeloid leukemia
- drug administration
- risk assessment
- cell proliferation
- deep learning
- climate change
- binding protein
- childhood cancer
- phase ii
- lymph node metastasis
- placebo controlled
- aortic dissection