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miR-10a as a therapeutic target and predictive biomarker for MDM2 inhibition in acute myeloid leukemia
Thi Thanh Vu1, Friedrich Stölzel2, Kristy W Wang1
1Blood, Stem Cell, and Cancer Research Programme, St Vincent's Centre for Applied Medical Research and Department of Haematology, St Vincent's Hospital, Sydney, NSW, Australia.
Abstract:
Pharmacological 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.
Insights
MicroRNA miR-10a overexpression in acute myeloid leukemia (AML) predicts response to MDM2 inhibitors. Inhibiting miR-10a enhances treatment efficacy by promoting apoptosis, suggesting its use as a biomarker and therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- MDM2/4 inhibitors activate the tumor suppressor p53, showing promise for acute myeloid leukemia (AML) treatment.
- Current MDM2 inhibitor trials lack specific biomarkers, necessitating new strategies for patient stratification and treatment optimization.
Purpose of the Study:
- To investigate the role of microRNA miR-10a in AML pathogenesis and its potential as a predictive biomarker and therapeutic target for MDM2 inhibitor therapy.
- To explore the synergistic effects of miR-10a inhibition with MDM2 inhibitors and cytarabine in AML treatment.
Main Methods:
- Analysis of miR-10a expression and its downstream targets in AML cell lines and patient samples.
- Assessment of miR-10a expression as a predictor of response to MDM2 inhibitors and cytarabine.
- In vitro and in vivo studies evaluating the synergistic effects of miR-10a inhibition with Nutlin-3a and cytarabine.
Main Results:
- miR-10a expression and its downstream targets (MDM4, RB1CC1, TFAP2C, p53) were found to be predictive of MDM2 inhibitor sensitivity in AML.
- miR-10a expression correlated with patient response to MDM2 inhibitors combined with cytarabine.
- Inhibition of miR-10a synergized with MDM2 inhibitor Nutlin-3a and cytarabine, enhancing efficacy through p53-mediated apoptosis.
Conclusions:
- miR-10a serves as a potential biomarker for identifying AML patients likely to respond to cytarabine and MDM2 inhibition.
- Targeting miR-10a represents a promising therapeutic strategy to improve the efficacy of current AML treatments.
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