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

Area of Science:

• Oncology
• Molecular Biology
• Hematology

Background:

• Preclinical studies show bromodomain and extra-terminal protein inhibitors (BETi) are effective in myeloid neoplasms.
• BETi have shown limited efficacy as single agents in clinical trials.
• Combination therapies may enhance BETi efficacy in myeloid cancers.

Purpose of the Study:

• To identify effective BETi combination therapies for myeloid neoplasms.
• To nominate novel combination strategies for clinical investigation.

Main Methods:

• A chemical screen of BETi combinations using agents in clinical development.
• Validation in myeloid cell lines, heterotopic models, and patient-derived xenografts.
• Protein and RNA assays to elucidate synergistic mechanisms.

Main Results:

• PIM inhibitors (PIMi) demonstrated therapeutic synergy with BETi in myeloid leukemia models.
• BETi treatment increases PIM kinase, which drives resistance to BETi and sensitivity to PIMi.
• miR-33a downregulation mediates PIM1 upregulation, and GM-CSF hypersensitivity is a marker for combination therapy sensitivity in CMML.

Conclusions:

• PIM kinase inhibition is a potential strategy to overcome BETi resistance in myeloid neoplasms.
• The combination of BETi and PIMi warrants further clinical investigation.