Role of BCL-2 Family Proteins in Cancer: Therapeutic Advancements and Challenges
A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".
Deadline for manuscript submissions: 30 June 2026 | Viewed by 1273
Special Issue Editor
2. Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229 USA
Interests: gastrointestinal and pulmonary cancers; BCL-2 family proteins; drug discovery and development; drug resistance; targeted protein degradation; proteolysis-targeting chimeras (PROTACs); cellular senescence; drug repurposing
Special Issue Information
Dear Colleagues,
The BCL-2 family of proteins plays a pivotal role in regulating cellular apoptosis, a process of programmed cell death that is critical to the maintenance of tissue homeostasis. These proteins are categorized into pro-apoptotic and anti-apoptotic members, which promote and inhibit cell death, respectively. An intricate balance between these two groups of BCL-2 proteins is important for maintaining tissue homeostasis, and their imbalance leads to cancer. The anti-apoptotic proteins (such as BCL-2, BCL-xL, and MCL-1) inhibit cell death by binding to pro-apoptotic proteins (such as BAK, BAX, BAD, and BIM). In cancer, overexpression of anti-apoptotic proteins is a common mechanism through which cancer cells evade apoptosis, leading to uncontrolled cell proliferation and tumor survival. This dysregulation is evident in hematological malignancies and many solid tumors, making the BCL-2 family of proteins a key target for cancer therapeutics. In addition, the overexpression of these proteins provides resistance to many chemotherapy and targeted drugs in cancer.
Recent therapeutic advancements have focused on developing small-molecule inhibitors (such as BH3 mimetics) that specifically target BCL-2 proteins, with drugs like venetoclax (ABT-199, a selective BCL-2 inhibitor) showing significant promise in treating certain hematological malignancies (such as chronic lymphocytic leukemia and acute myeloid leukemia). However, these therapies face challenges, including the development of resistance and significant toxicities, particularly in terms of on-target effects such as thrombocytopenia and cardiotoxicity induced by BCL-xL and MCL-1 inhibitors, respectively. The balance between effectively targeting cancer cells while minimizing damage to normal cells remains a delicate and ongoing challenge. Additionally, the heterogeneity among different cancers and within individual tumors complicates treatment, as varying expression levels of BCL-2 family proteins can influence drug sensitivity and efficacy.
Given the critical role of BCL-2 proteins, efforts are being made to selectively target BCL-2 family proteins in tumor cells, such as by using proteolysis-targeting chimeras (PROTACs), which exploit tumor-expressing E3 ligases for selective degradation of BCL-xL in tumor cells that minimizes platelet toxicity while improving antitumor efficacy. In addition, approaches to targeted drug delivery in tumor cells, such as by using pro-drugs, have also shown promise to reduce normal tissue toxicities while maintaining or improving antitumor potencies. Despite these efforts, safely targeting BCL-2 family proteins is still challenging. This Special Issue is soliciting manuscript submissions on novel therapeutic approaches to target BCL-2 family proteins, combination therapies, strategies to overcome resistance, and the development of next-generation inhibitors with reduced toxicity profiles. Additionally, studies focusing on biomarker development to better predict response to BCL-2-targeted therapies would be of high interest.
Dr. Sajid Khan
Guest Editor
Manuscript Submission Information
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Keywords
- BCL-2 family proteins
- apoptosis
- BH3 mimetics
- thrombocytopenia
- proteolysis-targeting chimeras
- drug resistance
- combination therapy
- targeted drug delivery
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