New research using human tissue samples and mouse models has identified the source of resistance of leukemia cells to venetoclax, a widely prescribed drug for acute myeloid leukemia. According to the study published in Cancer Discovery, the rapid increase in the breakdown and turnover of mitochondria helps leukemia cells evade the drug’s effects. Mitophagy, a process that prevents damaged mitochondria from sending “death signals,” enables leukemia cells to evade the killing effects of venetoclax. The study suggests that combining BH3 mimetics like venetoclax with MFN2 or general mitophagy inhibitors could possibly serve as a future therapy for acute myeloid leukemia. The research team plans to design a clinical trial to test whether chloroquine, when used in combination with venetoclax, prevents drug resistance in people with acute myeloid leukemia.
Acute myeloid leukemia is notoriously difficult to treat, with fewer than a third of those affected living longer than five years after their diagnosis, so it is important to maximize the impact of existing therapies. Current treatments include chemotherapy and a limited number of targeted drug therapies. Bone marrow transplantation has also been used when other options fail.
Funding support for the study was provided by National Institutes of Health grants alongside the Leukemia & Lymphoma Society and AstraZeneca, which provided several of the BH3 mimetic drugs used in these experiments.
