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Ref Type Journal Article
PMID (30206163)
Authors Stubbs MC, Burn TC, Sparks R, Maduskuie T, Diamond S, Rupar M, Wen X, Volgina A, Zolotarjova N, Waeltz P, Favata M, Jalluri R, Liu H, Liu XM, Li J, Collins R, Falahatpisheh N, Polam P, DiMatteo D, Feldman P, Dostalik V, Thekkat P, Gardiner C, He X, Li Y, Covington M, Wynn R, Ruggeri B, Yeleswaram S, Xue CB, Yao W, Combs AP, Huber R, Hollis G, Scherle P, Liu PCC
Title The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 25
Issue 1
Date 2019 01 01
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
INCB054329 INCB-054329 BET Inhibitor (Pan) 27 INCB054329 is BET inhibitor, which results in decreased expression of BET protein-regulated genes including MYC, potentially leading to decreased tumor cell proliferation (PMID: 30206163)
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown multiple myeloma not applicable INCB054329 + Ruxolitinib Preclinical - Cell line xenograft Actionable In a preclinical study, INCB054329 and Jakafi (ruxolitinib) demonstrated synergy in a myeloma cell line in culture, resulting in decreased viability, increased apoptosis, and increased inhibition of STAT3 phosphorylation, and treatment with the combination of INCB054329 and Jakafi (ruxolitinib) resulted in increased efficacy in myeloma cell line xenograft models over either agent alone, with tumor regressions in 5/8 animals (PMID: 30206163). 30206163
Unknown unknown multiple myeloma not applicable INCB054329 Preclinical - Cell line xenograft Actionable In a preclinical study, INCB054329 treatment reduced MYC expression and proliferation of myeloma cell lines in culture, and inhibited tumor growth in myeloma cell line xenograft models (PMID: 30206163). 30206163
Unknown unknown multiple myeloma not applicable INCB054329 + Pemigatinib Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of INCB054329 and Pemazyre (pemigatinib) decreased MYC expression and FGFR3 signaling and inhibited tumor growth in a t(4;14)-positive myeloma cell line xenograft model, demonstrating increased efficacy over either agent alone (PMID: 30206163). 30206163
Unknown unknown multiple myeloma not applicable INCB054329 + Itacitinib Preclinical - Cell line xenograft Actionable In a preclinical study, INCB054329 and Itacitinib (INCB039110) demonstrated synergy in a myeloma cell line in culture, resulting in decreased viability, increased apoptosis, and increased inhibition of STAT3 phosphorylation, and treatment with the combination of INCB054329 and Itacitinib (INCB039110) resulted in increased efficacy in myeloma cell line xenograft models over either agent alone (PMID: 30206163). 30206163