Cebpβ/IL1/TNFα Positive Feedback Loop Drives Drug Resistance of BCL2 and MDM2 Inhibitors in Monocytic Leukemia Cells

Introduction:Ventoclax-based combinations have emerged as a new standard of care for patients with acute myeloid leukemia (AML) who are not suitable for intense chemotherapy. Not all patients respond to these treatments, and those who do may relapse. MDM2 inhibitors are promising therapeutics for treating TP53 wild-type tumors, including most de novo AML cases, with numerous compounds currently in pre-clinical and clinical evaluation. However, clinical trials of MDM2 inhibitors have shown modest and variable clinical activity. Functional genomic data showed that monocytic leukemia (FAB M4/M5) is resistant to venetoclax-based therapies and MDM2 inhibitors. Notably, venetoclax and an MDM2 inhibitor, idasanutlin, demonstrated a strong positive correlation in the Beat AML cohort.