Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML.

Autor:	Letson CT; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Balasis ME; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Newman H; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Binder M; Division of Hematology, Mayo Clinic, Rochester, Minnesota.; Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota., Vedder A; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Kinose F; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Ball M; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Kruer T; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Quintana A; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Lasho TL; Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota., Finke CM; Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota., Almada LL; Division of Oncology Research, Schulze Center for Novel Therapeutics, Department of Oncology, Mayo Clinic, Rochester, Minnesota., Grants JM; Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC., Zhang G; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Fernandez-Zapico ME; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Gaspar-Maia A; Division of Hematology, Mayo Clinic, Rochester, Minnesota.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Lancet J; Malignant Hematology Department, Moffitt Cancer Center, Tampa, Florida., Komrokji R; Malignant Hematology Department, Moffitt Cancer Center, Tampa, Florida., Haura E; Department of Drug Discovery, H Lee Moffitt Cancer Center, Tampa, Florida., Sallman DA; Malignant Hematology Department, Moffitt Cancer Center, Tampa, Florida., Reuther GW; Department of Molecular Oncology, H Lee Moffitt Cancer Center, Tampa, Florida., Karsan A; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC., Rix U; Department of Drug Discovery, H Lee Moffitt Cancer Center, Tampa, Florida., Patnaik MM; Division of Hematology, Mayo Clinic, Rochester, Minnesota.; Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota., Padron E; Malignant Hematology Department, Moffitt Cancer Center, Tampa, Florida.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Aug 01; Vol. 29 (15), pp. 2919-2932.
DOI:	10.1158/1078-0432.CCR-22-3929
Abstrakt:	Purpose: Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor single-agent activity in clinical trials. Several studies suggest that combination with other anticancer 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 patient-derived xenograft models of disease. We used 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. Furthermore, 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. Conclusions: Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data support further clinical investigation of this combination. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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