The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies.

Abstract

Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials. We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations. In addition to c-MYC, INCB054329 decreased expression of oncogenes <i>FGFR3</i> and <i>NSD2/MMSET/WHSC1,</i> which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of <i>FGFR3</i> sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor <i>in vivo</i>. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK-STAT signaling and synergized to inhibit myeloma cell growth <i>in vitro</i> and <i>in vivo</i>. This combination potentiated tumor growth inhibition <i>in vivo</i>, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone. Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.