Targeting BET proteins downregulates miR-33a to promote synergy with PIM inhibitors in CMML
| Autor: | Christopher T. Letson, Maria E. Balasis, Hannah Newman, Moritz Binder, Alexis Vedder, Fumi Kinose, Markus Ball, Traci Kruer, Ariel Quintana, Terra L. Lasho, Christy M. Finke, Luciana L. Almada, Jennifer M. Grants, Guolin Zhang, Martin E. Fernandez-Zapico, Alexandre Gaspar-Maia, Jeffrey Lancet, Rami Komrokji, Eric Haura, David A. Sallman, Gary W. Reuther, Aly Karsan, Uwe Rix, Mrinal M. Patnaik, Eric Padron |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Clinical Cancer Research. |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Background: Preclinical studies in myeloid neoplasms have demonstrated efficacy of Bromodomain and Extra-Terminal protein inhibitors (BETi). However, BETi demonstrate poor single agent activity in clinical trials. Several studies suggest that combination with other anti-cancer inhibitors may enhance the efficacy of BETi. Experimental Design: To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and PDX models of disease. We utilized standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models. Results: We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Further, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy. Conclusion: Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data supports further clinical investigation of this combination. |
| Databáze: | OpenAIRE |
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