Reducing mitophagy may help to reduce to BH3 mimetic resistance in acute myeloid leukemia (AML), which may lead to improved clinical outcomes, according to research published in Cancer Discovery.
Clinical data have shown, however, that prolonged use of venetoclax with hypomethylating agents (HMAs) leads to treatment resistance, with unknown underlying causes. For this study of patient-derived models, researchers evaluated the molecular underpinnings for treatment resistance to BH3 mimetics among patients with AML.
Analysis of genome-wide CRISPR/Casp9 screens showed that mitophagy may sensitize AML cells to targets of BH3 mimetics via regulators, including the protein MFN2. The authors noted, furthermore, that MFN2 protein levels had a positive correlation with drug resistance in evaluated cell lines.
Cell pro-survival mechanisms, including enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux, appear to be linked with BH3 mimetic insensitivity.
Finally, targeting MFN2 appears to work with BH3 mimetics by impairing mitochondrial clearance and enhancing AML cell apoptosis, potentially representing a new, synergistic therapeutic approach in this setting.
“Blocking MFN2 activity and the specific clearance of damaged mitochondria through mitophagy represents a powerful approach to overcome drug resistance in hematologic malignancies and other tumors,” the authors wrote in their report.
Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.
Glytsou C, Chen X, Zacharioudakis E, et al. Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia. Published online April 24, 2023. Cancer Discov. doi:10.1158/2159-8290.CD-22-0601