Decoding and unlocking the BCL-2 dependency of cancer cells

The balance between pro- and anti-apoptotic activities of BCL-2 family members is tipped towards survival in many cancer cells, thus allowing them to survive various stressful environments, tumour stress phenotypes and/or oncogene-induced death signals.As death signals may persist during tumour progression, cancer cells may be addicted to these survival mechanisms and be in a state of dependence on 'BCL-2-like' (BCL-2L) anti-apoptotic proteins.Survival of 'BCL-2L-dependent' cancer cells relies on the maintenance of protein–protein complexes in which the BH3 domain of some pro-apoptotic BCL-2 family members engages a hydrophobic groove at the surface of anti-apoptotic BCL-2L proteins.Structural characterization of the BH3-binding interface of anti-apoptotic BCL-2L proteins has led to the identification of small-molecule BH3 mimetics that disrupt key interactions and promote cancer cell apoptosis by on-target effects.A dual BCL-2 and BCL-XL inhibitor and a specific BCL-2 inhibitor have shown clinical activity in haematological malignancies. The dual inhibitor induces dose-limiting thrombocytopenia owing to BCL-XL inhibition.Finely-tuned inhibition of BCL-XL and of MCL1 in cancer cells by new and selective drugs remains a challenge and a necessity.Understanding the exact effects of inhibitors on endogenous (membrane-localized) complexes, identifying predictive biomarkers for drug efficacy and circumscribing the global biological effects of these compounds is also required.