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BCL-2 inhibitors in hematological malignancies: biomarkers that predict response and management strategies
Mariam Markouli1, Maria N Pagoni2, Panagiotis Diamantopoulos3
1Department of Internal Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, United States.
Abstract:
Apoptosis is an essential characteristic of cancer and its dysregular promotes tumor growth, clonal evolution, and treatment resistance. B-cell lymphoma-2 (BCL-2) protein family members are key to the intrinsic, mitochondrial apoptotic pathway. The inhibition of the BCL-2 family pro-survival proteins, which are frequently overexpressed in B-cell malignancies and pose a fundamental carcinogenic mechanism has been proposed as a promising therapeutic option, with venetoclax (ABT-199) being the first FDA-approved BCL-2 inhibitor. Unfortunately, although BCL-2 inhibition has shown remarkable results in a range of B-cell lymphoid cancers as well as acute myeloid leukemia (AML), the development of resistance significantly reduces response rates in specific tumor subtypes. In this article, we explain the role of BCL-2 family proteins in apoptosis and their mechanism of action that justifies their inhibition as a potential treatment target in B-cell malignancies, including chronic lymphocytic leukemia, multiple myeloma, B-cell lymphomas, but also AML. We further analyze the tumor characteristics that result in the development of intrinsic or inherited resistance to BCL-2 inhibitors. Finally, we focus on the biomarkers that can be used to predict responses to treatment in the name of personalized medicine, with the goal of exploring alternative strategies to overcome resistance.
Insights
B-cell lymphoma-2 (BCL-2) protein inhibition shows promise for treating certain cancers. However, resistance limits effectiveness, necessitating research into biomarkers and alternative strategies for personalized medicine.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Apoptosis is crucial in cancer; its dysregulation fuels tumor growth and treatment resistance.
- The B-cell lymphoma-2 (BCL-2) protein family regulates the intrinsic mitochondrial apoptotic pathway.
- Overexpressed pro-survival BCL-2 proteins are a key mechanism in B-cell malignancies.
Purpose of the Study:
- To elucidate the role of BCL-2 family proteins in apoptosis and their therapeutic inhibition.
- To analyze mechanisms of intrinsic and acquired resistance to BCL-2 inhibitors.
- To identify biomarkers for predicting treatment response and explore resistance-overcoming strategies.
Main Methods:
- Review of the literature on BCL-2 protein family function in apoptosis.
- Analysis of BCL-2 inhibitor mechanisms and resistance pathways.
- Exploration of biomarkers for personalized medicine approaches.
Main Results:
- BCL-2 inhibition is a validated therapeutic strategy for B-cell malignancies and AML.
- Resistance to BCL-2 inhibitors develops in specific tumor subtypes, reducing efficacy.
- Biomarkers are crucial for predicting patient response and guiding treatment decisions.
Conclusions:
- Targeting BCL-2 offers a promising therapeutic avenue for B-cell cancers and AML.
- Understanding resistance mechanisms is vital for improving patient outcomes.
- Personalized medicine approaches utilizing biomarkers and alternative strategies are essential to overcome resistance.
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