The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies
Purpose: Bromodomain and extraterminal domain (BET) proteins regulate the expression of numerous cancer-connected genes and pathways BET inhibitors have shown activity in diverse types of hematologic and solid tumors. We report the preclinical portrayal of INCB054329, a structurally distinct BET inhibitor that’s been investigated in phase I numerous studies.
Experimental design: We used multiple myeloma models to research vulnerabilities produced by INCB054329 treatment that may inform rational combinations.
Results: Additionally to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, that are deregulated in t(414)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(414)-positive cell line OPM-2 to combined treatment having a fibroblast growth factor receptor inhibitor in vivo. Additionally, we reveal that BET inhibition across multiple myeloma cell lines led to covered up interleukin (IL)-6 Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. INCB054329 displaced binding of BRD4 towards the promoter of IL6 receptor (IL6R) resulting in reduced amounts of IL6R and reduced signaling through STAT3. In conjunction with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK-STAT signaling and synergized to hinder myeloma cell development in vitro as well as in vivo. This mixture potentiated tumor growth inhibition in vivo, even just in the MM1.S type of myeloma that isn’t intrinsically responsive to JAK inhibition alone.
Conclusions: Preclinical data reveal insights into vulnerabilities produced in myeloma cells by BET protein inhibition and potential strategies that may be leveraged in studies to boost the game of INCB054329.