Acute myeloid leukemia (AML) is a rapidly progressing blood cancer that often recurs after treatment. In a paper published Feb. 17 in the journal Leukemia, Aditi Shastri, M.B.B.S., first author Samarpana Chakraborty, Ph.D., and colleagues describe a new approach to treating AML that has become resistant to the primary treatment, venetoclax.

Dr. Shastri’s team previously showed that abnormally high levels of the protein STAT3 promote the onset of AML. In this study, the researchers created a new mouse model in which STAT3 is permanently switched on in blood-forming cells. This caused the mice to rapidly develop an AML-like disease, demonstrating that excessive STAT3 activity alone is sufficient to cause the disease. In addition, the investigators found that patients who were treated with venetoclax and had become resistant to that treatment had an increased expression of STAT3. After examining cells from these patients, the researchers observed previously unrecognized defects in mitochondria, the energy-producing structures within cells, that were linked to excessive STAT3 activity. Earlier efforts to halt AML by inhibiting STAT3 production hadn’t worked, so Dr. Shastri’s team examined a different approach.

The Shastri team tested a new type of drug, a targeted protein degrader called KT-333, that removes the STAT3 protein rather than simply blocking it. The scientists found that KT-333 corrected the mitochondria defects they’d observed in cells of venetoclax-resistant AML patients and killed those resistant cells in mice. The findings point to a promising new strategy for overcoming drug resistance in aggressive AML that is ready to be tested clinically in patients.

Dr. Shastri is associate professor of oncology, of medicine and of developmental & molecular biology at Einstein and a member of the Stem Cell and Cancer Biology Research Program and associate director of Translational Research in the Blood Cancer Institute at the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center. Dr. Chakraborty is an instructor of oncology. Additional authors are Keisuke Ito, M.D., Ph.D., and Claudia Morganti, Ph.D., at Einstein, and Sergei Koralov, Ph.D., at NYU.