The BCL2 Family: Key Mediators of the Apoptotic Response to Targeted Anticancer Therapeutics

Abstract

The ability of cancer cells to suppress apoptosis is critical for carcinogenesis. The BCL2 family proteins comprise the sentinel network that regulates the mitochondrial or intrinsic apoptotic response. Recent advances in our understanding of apoptotic signaling pathways have enabled methods to identify cancers that are "primed" to undergo apoptosis, and have revealed potential biomarkers that may predict which cancers will undergo apoptosis in response to specific therapies. Complementary efforts have focused on developing novel drugs that directly target antiapoptotic BCL2 family proteins. In this review, we summarize the current knowledge of the role of BCL2 family members in cancer development and response to therapy, focusing on targeted therapeutics, recent progress in the development of apoptotic biomarkers, and therapeutic strategies designed to overcome deficiencies in apoptosis.

Significance: Apoptosis, long known to be important for response to conventional cytotoxic chemotherapy, has more recently been shown to be essential for the efficacy of targeted therapies. Approaches that increase the likelihood of a cancer to undergo apoptosis following therapy may help improve targeted treatment strategies. Cancer Discov; 5(5); 475-87. ©2015 AACR.

Figure 1. The intrinsic apoptotic pathway is regulated by BCL-2 family proteins at the level of the mitochondria

Multiple cellular stressors modulate the expression levels of pro- and anti-apoptotic BCL-2 family proteins (red and green respectively), leading to the activation of BAX and/or BAK and mitochondrial depolarization.

Figure 2. Targeted therapies inhibit oncogenic kinase signaling cascades and modulate BCL-2 family proteins to induce apoptosis

Examples of commonly occuring cancers driven by specific oncogenic driver mutations that result in constitutively activated downstream kinase signaing pathways and suppression of the mitochondrial apoptotic pathway. By inhibiting these pathways, targeted therapies lead to upregulation of pro-apoptotic BH3-only proteins and/or downregulation of pro-survival BCL-2 family proteins, ultimately inducing apoptosis. (See references: EGFR (84, 87, 88, 105, 108), BRAF (89, 106, 181), KRAS (90), CML (76, 91, 113))

Figure 3. Strategies for enhancing the pro-apoptotic activity of BIM

Demethylating agents or histone deacetylase (HDAC) inhibitors may overcome epigenetic reppression of BIM transcription, whereas MEK inhibitors (e.g. trametinib) decrease BIM degradation—all leading to increased cellular BIM protein levels and increased activation of BAX. BCL-2/BCL-XL inhibitors (e.g. navitoclax) block the ability for anti-apoptotic BCL-2 family members like BCL-2 and BCL-XL to neutralize BIM.