miR-10a as a therapeutic target and predictive biomarker for MDM2 inhibition in acute myeloid leukemia

• DOI: 10.1038/s41375-020-01095-z
• Publication Date: 2020-12-01T18:34:36Z
• Authors: Thi Thanh Vu; Friedrich Stölzel; Kristy W. Wang; Christoph Röllig; Melinda L. Tursky; Timothy J. Molloy; David D. Ma
• Keywords: Myeloid; 32 Biomedical and Clinical Sciences; Apoptosis; anzsrc-for: 1103 Clinical Sciences; Piperazines; Mice; Mice, Inbred NOD; 2.1 Biological and endogenous factors; Precision Medicine; Cancer; Pediatric; 0303 health sciences; Tumor; Leukemia; Cytarabine; Imidazoles; Proto-Oncogene Proteins c-mdm2; Hematology; 3. Good health; Leukemia, Myeloid, Acute; 5.1 Pharmaceuticals; anzsrc-for: 3202 Clinical sciences; Female; 570; Childhood Leukemia; Pediatric Cancer; 610; Antineoplastic Agents; Acute; Article; Cell Line; 03 medical and health sciences; Rare Diseases; anzsrc-for: 32 Biomedical and Clinical Sciences; Clinical Research; Cell Line, Tumor; Genetics; Autophagy; Biomarkers, Tumor; Animals; Humans; anzsrc-for: 3211 Oncology and Carcinogenesis; anzsrc-for: 1112 Oncology and Carcinogenesis; 3211 Oncology and Carcinogenesis; MicroRNAs; Orphan Drug; Inbred NOD; Biomarkers; anzsrc-for: 3201 Cardiovascular medicine and haematology

AbstractPharmacological inhibition of MDM2/4, which activates the critical tumor suppressor p53, has been gaining increasing interest as a strategy for the treatment of acute myeloid leukemia (AML). While clinical trials of MDM2 inhibitors have shown promise, responses have been confined to largely molecularly undefined patients, indicating that new biomarkers and optimized treatment strategies are needed. We previously reported that the microRNA miR-10a is strongly overexpressed in some AML, and demonstrate here that it modulates several key members of the p53/Rb network, including p53 regulator MDM4, Rb regulator RB1CC1, p21 regulator TFAP2C, and p53 itself. The expression of both miR-10a and its downstream targets were strongly predictive of MDM2 inhibitor sensitivity in cell lines, primary AML specimens, and correlated to response in patients treated with both MDM2 inhibitors and cytarabine. Furthermore, miR-10a inhibition induced synergy between MDM2 inhibitor Nutlin-3a and cytarabine in both in vitro and in vivo AML models. Mechanistically this synergism primarily occurs via the p53-mediated activation of cytotoxic apoptosis at the expense of cytoprotective autophagy. Together these findings demonstrate that miR-10a may be useful as both a biomarker to identify patients most likely to respond to cytarabine+MDM2 inhibition and also a druggable target to increase their efficacy.