Chemotherapy drugs and anti-cancer drugs called BH3 mimetics work by damaging cancer cells severely enough to make them undergo apoptosis, or programmed cell death. Most often the drugs’ way of killing cancer cells is to activate BAX, a cellular protein dubbed the “executioner protein.”

In a study published online on December 16 in Nature Communications, Evripidis Gavathiotis, Ph.D., and colleagues reported that BAX forms dimers (two BAX molecules bound to each other) in various cancer cells and that this form of BAX is associated with resistance to apoptosis. Interestingly, some patients with acute myeloid leukemia (AML) who are treated with the BH3 mimetic venetoclax relapse because their cancer cells develop mutations that can cause BAX to form dimers. The Gavathiotis team discovered new small molecules that activate the BAX dimer and, as a result, can induce apoptosis in treatment-resistant AML cells, either as single agents or combined with venetoclax or doxorubicin, a chemotherapy drug. This strategy could be applied to treating various types of cancer or to overcome drug resistance caused by the formation of BAX dimers.

Dr. Gavathiotis is professor of biochemistry, of medicine, and of oncology, and co-leader of the National Cancer Institute–designated Montefiore Einstein Comprehensive Cancer Center’s Cancer Therapeutics Program.  The paper’s first author is Nadege Gitego, Ph.D., previously a PhD student in the laboratory of Dr. Gavathiotis.