Many cases of acute myeloid leukemia (AML) and other cancers become incurable when they develop resistance to chemotherapy. Most resistance research has focused on genetic mutations that emerge over time and contribute to cancer-cell survival. In novel findings published on July 1 in Blood Cancer Discovery, researchers at Montefiore Einstein Comprehensive Cancer Center (MECCC) and collaborators have discovered how AML cells quickly adapt to cytarabine, one of the most commonly used chemotherapy drugs for the disease. In pre-clinical studies, blocking this early response made treatment more effective, suggesting a promising new strategy for preventing drug resistance in AML and potentially in other cancers.

The researchers found that soon after AML cell lines and patients' leukemia cells were exposed to cytarabine, many of those cells sharply increased their production of messenger RNA (mRNA), the molecules that carry genetic instructions for making proteins. Cells that mounted this response were more likely to develop resistance to the drug. Further analyses, including through specialized assays at single-molecule resolution, revealed that cytarabine rapidly and specifically boosted production of mRNA from genes encoding transcription factors, specialized proteins that help control which genes are turned on or off. Cytarabine triggered a previously unrecognized rapid gene activation response that helped AML cells survive treatment.

Inhibiting RNA production before and during treatment reduced the development of drug resistance in AML cell lines, patients’ leukemia cells, and animal models of the disease. The findings suggest that combining chemotherapy with drugs that block this early response could provide a new strategy for overcoming one of the greatest challenges in cancer treatment: chemotherapy resistance. Efforts to advance these highly promising findings towards testing in clinical trials are ongoing.

The study was led by Ulrich Steidl, M.D., Ph.D., professor and chair of cell biology, professor of oncology and of medicine, and director of MECCC. Co-author Amit Verma, M.B.B.S., is professor of oncology, of medicine and of developmental and molecular biology and deputy director of MECCC.