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

• DOI: 10.1158/1078-0432.c.6529230.v1
• Publication Date: 2023-04-01T06:20:32Z
• Authors: Matthew C. Stubbs; Timothy C. Burn; Richard Sparks; Thomas Maduskuie; Sharon Diamond; Mark Rupar; Xiaoming Wen; Alla Volgina; Nina Zolotarjova; Paul Waeltz; Margaret Favata; Ravi Jalluri; Huiqing Liu; Xuesong Mike Liu; Jun Li; Robert Collins; Nikoo Falahatpisheh; Padmaja Polam; Darlise DiMatteo; Patricia Feldman; Valerie Dostalik; Pramod Thekkat; Christine Gardiner; Xin He; Yanlong Li; Maryanne Covington; Richard Wynn; Bruce Ruggeri; Swamy Yeleswaram; Chu-Biao Xue; Wenqing Yao; Andrew P. Combs; Reid Huber; Gregory Hollis; Peggy Scherle; Phillip C.C. Liu
• Keywords: Ruxolitinib; BET inhibitor; BRD4

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