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

Author:

Letson Christopher T.1ORCID,Balasis Maria E.1ORCID,Newman Hannah1ORCID,Binder Moritz23ORCID,Vedder Alexis1ORCID,Kinose Fumi1ORCID,Ball Markus1ORCID,Kruer Traci1ORCID,Quintana Ariel1ORCID,Lasho Terra L.3ORCID,Finke Christy M.3ORCID,Almada Luciana L.4ORCID,Grants Jennifer M.5ORCID,Zhang Guolin1ORCID,Fernandez-Zapico Martin E.2ORCID,Gaspar-Maia Alexandre26ORCID,Lancet Jeffrey7ORCID,Komrokji Rami7ORCID,Haura Eric8ORCID,Sallman David A.7ORCID,Reuther Gary W.9ORCID,Karsan Aly10ORCID,Rix Uwe8ORCID,Patnaik Mrinal M.23ORCID,Padron Eric7ORCID

Affiliation:

1. 1H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

2. 2Division of Hematology, Mayo Clinic, Rochester, Minnesota.

3. 3Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.

4. 4Division of Oncology Research, Schulze Center for Novel Therapeutics, Department of Oncology, Mayo Clinic, Rochester, Minnesota.

5. 5Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC.

6. 6Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

7. 7Malignant Hematology Department, Moffitt Cancer Center, Tampa, Florida.

8. 8Department of Drug Discovery, H Lee Moffitt Cancer Center, Tampa, Florida.

9. 9Department of Molecular Oncology, H Lee Moffitt Cancer Center, Tampa, Florida.

10. 10Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC.

Abstract

Abstract 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.

Funder

National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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