BCL-2 Emerges as an Attractive Target in Solid and Hematologic Cancers

Erin Burns, PhD
Published: Tuesday, Mar 05, 2019
The gene encoding B-cell lymphoma-2 (BCL-2) was identified more than 30 years ago in a patient with follicular lymphoma (FL) who had a chromosomal translocation that led to dysregulated BCL-2 expression.1 When the BCL-2 gene product was reported to block cell death instead of enhancing cell proliferation, which was the expected action of oncogenes, the link among BCL-2, apoptosis, and cancer was established.2,3 This finding led to the idea that impaired apoptosis was an important feature required for tumorigenesis.4

High BCL-2 expression levels discovered in hematologic malignancies have led to numerous clinical investigations, paving the way for the initial approval in chronic lymphocytic leukemia (CLL) for venetoclax (Venclexta), the first BCL-2 inhibitor indicated for cancer treatment, in 2016.5 Additional investigations of venetoclax are ongoing in hematologic malignances, and new drugs are in development. Meanwhile, investigators are hoping to develop BCL-2 as an actionable target in solid tumors, with recent findings in venetoclax studies providing potential support for these investigations.

However, there are challenges for targeting BCL-2 in both hematologic and solid tumors. Resistance to BH3 mimetics that target BCL-2 and BCL-2/BCL-XL has been observed in vitro and in vivo.6-8 There are also altered cellular activities that have not been eliminated via BCL-2 protein targeting. In models of γ-irradiation–induced thymic lymphoma, overexpression of BCL-2, which is usually considered to be a procancer event, protects against the development of tumors.9 It is unclear at this time whether these concerns will remain in clinical trials; however, promising study results support the potential of BH3 mimetics to dramatically improve survival in patients with various cancer types.

Role of BCL-2 in Cancer

The BCL-2 family proteins are important for regulation of cell death at both the mitochondria and the endoplasmic reticulum. The proteins function to regulate mitochondrial outer membrane permeabilization through a coordinated series of protein–protein and protein–membrane interactions that are associated with protein conformational changes that control pore formation in organelle membranes.10,11 When BCL-2 is overexpressed, it blocks BAX, an apoptotic protein, and prevents mitochondrial pore formation and inhibits the release of cytochrome C, which leads to inhibited or reduced cell death.12

To maintain proliferation of cancer cells, tumors must prevent apoptosis and are reliant on BCL-2 proteins to block cell death under environmental pressure from the immune system or chemotherapeutic agents. In these conditions, tumors have been said to be “BCL-2 addicted” and more susceptible to BCL-2 inhibitors.13 Hematologic cancers generally are more dependent on BCL-2, whereas solid tumors have been reported to be more dependent on other antiapoptotic proteins, including BCL-XL or MCL-1.14 Therefore, selective antagonism of BCL-2 family proteins provides an opportunity to treat tumors.

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Online CME Activities
TitleExpiration DateCME Credits
Oncology Consultations®: The Advancing Role of CAR T-Cell Therapies in Hematologic MalignanciesApr 30, 20191.5
Advances in™ Diagnostic Guidelines for Effective Clinical Decision - Making in the Management of Hematologic MalignanciesApr 30, 20191.5
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