Development of venetoclax for therapy of lymphoid malignancies

• Published in: Drug design, development and therapy development and therapy, 2017-01, Vol.11, p.685-694
• Main Authors: Zhu, Huayuan, Almasan, Alexandru
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Apoptosis; B-cell lymphoma; Bcl-2; Bcl-2 protein; Bcl-x protein; Bcl-xL; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cancer therapies; Chronic lymphocytic leukemia; Clinical trials; Clonal deletion; Cloning; Cyclin-dependent kinases; Cytotoxicity; Drug therapy; Gene amplification; Homology; Humans; Inhibitor drugs; Kinases; Leukemia; Lymphatic diseases; Lymphatic leukemia; Lymphocytes B; Lymphoma; Lymphoma, B-Cell - drug therapy; Mcl-1; Mcl-1 protein; Medical research; Multiple myeloma; Pathogenesis; Patients; Proteins; Review; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - therapeutic use; Targeted cancer therapy; Therapeutic applications; Therapy; Tumor cells; venetoclax
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S109325

B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications.