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 FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. 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 in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, 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.
Highlights
Bromodomain and extraterminal domain (BET) proteins comprise a family of four related proteins (BRD2, BRD3, BRD4, and BRDT), each harboring two tandem amino-terminal bromodomains (BD1 and BD2) that bind selectively to acetylated lysine residues
Association of BRD4 with chromatin is strongly enriched at large enhancer elements, called super-enhancers, which are frequently co-opted in tumor cells to drive expression of genes involved in cell proliferation, cell fate, and survival [3, 4]
We report that INCB054329 sensitizes myeloma cells both in vitro and in vivo to clinical Janus kinase inhibitors, such as ruxolitinib, by reducing interleukin-6 receptor expression, and to the phase II fibroblast growth factor receptor (FGFR) inhibitor INCB054828 in subsets of t(4;14) translocated myelomas with high fibroblast growth factor receptor 3 (FGFR3) expression
Summary
Bromodomain and extraterminal domain (BET) proteins comprise a family of four related proteins (BRD2, BRD3, BRD4, and BRDT), each harboring two tandem amino-terminal bromodomains (BD1 and BD2) that bind selectively to acetylated lysine residues. BET proteins regulate the expression of an array of genes by binding to highly acetylated histone tails at the promoters and enhancers of target genes and by recruiting transcriptional complexes including the super-elongation complex and the protein. Association of BRD4 with chromatin is strongly enriched at large enhancer elements, called super-enhancers, which are frequently co-opted in tumor cells to drive expression of genes involved in cell proliferation, cell fate, and survival [3, 4]. BRD2, BRD3, and BRD4 have been shown to control the inflammatory response in models of acute inflammation by regulating the expression of proinflammatory modulators such as interleukin (IL)-6 and tumor necrosis factor (TNF)a [8, 10]. Tumor-associated inflammation is a hallmark of cancer, and elevated levels of proinflammatory proteins, including IL6, have been shown to promote multiple aspects of tumorigenesis. Antitumor activity of BET inhibitors may result from modulation of inflammation in addition to direct effects on the tumor cell
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