New drug combination restores ability of leading treatment to signal for death of blood cancer cells - Video

New research using human tissue samples and mouse models has found that resistance of leukemia cells to a widely prescribed drug called venetoclax occurs because of a rapid increase in the breakdown and turnover of mitochondria, structures inside the cell that help power its functions. In addition to their role in producing energy, mitochondria also tell cells to die under certain adverse conditions.

Led by scientists at NYU Langone Health and its Perlmutter Cancer Center, the study showed that mitophagy helps leukemia cells to evade the killing effects of venetoclax, a drug in a class of medications known as BH3 mimetics.

Researchers found that the levels of several genes associated with mitophagy were increased in 20 leukemia patient samples compared with normal controls. The level of these genes was even higher in samples from leukemia patients with drug resistance than in those leukemic patients who were not. Particularly notable was the increased expression of the gene for Mitofusin-2 (MFN2), which codes for a key protein in the outer mitochondrial membrane.

Further experiments using mice into which bone marrow from acute myeloid leukemia patients was transplanted showed that the drug chloroquine, a known mitophagy inhibitor, restored the ability of venetoclax to kill the cancer cells.

Speaking about other study results, the researchers say they not only found that MFN2 was overly active in people with drug-resistant disease, but also that cancer cells exposed to similar cell-death-inducing compounds demonstrated a doubling in mitophagy rates.

Additional testing in cancer cells engineered to lack MFN2 showed increased sensitivity to drugs similar to venetoclax compared with cells that had functional MFN2. The new study and previous research by the team showing misshapen mitochondria in drug-resistant leukemic cells confirmed that increased mitophagy was the source of the problem.

Reference:

Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia,Cancer Discovery,DOI: 10.1158/2159-8290.CD-22-0601