Rational combination strategies to enhance venetoclax activity and overcome resistance in hematologic malignancies.

Abstract

Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies. As in the case of essentially all targeted agents, intrinsic or acquired resistance to this agent generally occurs, prompting the search for new strategies capable of circumventing this problem. A logical approach to this challenge involves rational combination strategies designed to disable preexisting or induced compensatory survival pathways. Many of these strategies involve downregulation of Mcl-1, a pro-survival Bcl-2 family member that is not targeted by venetoclax, and which often confers resistance to this agent. Given encouraging clinical results involving venetoclax in both lymphoid and myeloid malignancies, it is likely that such combination approaches will be incorporated into the therapeutic armamentarium for multiple hematologic malignancies in the near future.

• Authors: Steven Grant
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 59 Issue 6 Pg. 1292-1299 (06 2018) ISSN: 1029-2403 [Electronic] United States
• PMID: 28838268 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Biomarkers, Tumor
• Bridged Bicyclo Compounds, Heterocyclic
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• venetoclax

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Biomarkers, Tumor
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage)
• Cell Survival (genetics)
• Drug Resistance, Neoplasm (genetics)
• Hematologic Neoplasms (diagnosis, drug therapy, genetics, metabolism)
• Humans
• Molecular Targeted Therapy
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• Sulfonamides (administration & dosage)