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

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations.

RESULTS:

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.

CONCLUSIONS:

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.

• 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 1 Pg. 300-311 (01 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30206163 (Publication Type: Journal Article)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• BRD4 protein, human
• Cell Cycle Proteins
• IL6R protein, human
• INCB054329
• MYC protein, human
• Organic Chemicals
• Proteins
• Proto-Oncogene Proteins c-myc
• Receptors, Interleukin-6
• Repressor Proteins
• STAT3 Transcription Factor
• Transcription Factors
• bromodomain and extra-terminal domain protein, human
• Histone-Lysine N-Methyltransferase
• NSD2 protein, human
• FGFR3 protein, human
• Receptor, Fibroblast Growth Factor, Type 3
• Janus Kinases

Topics

• Animals
• Cell Cycle Proteins (antagonists & inhibitors, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterografts
• Histone-Lysine N-Methyltransferase (genetics)
• Humans
• Janus Kinases (genetics)
• Mice
• Multiple Myeloma (drug therapy, genetics, pathology)
• Organic Chemicals (pharmacology)
• Protein Binding (drug effects)
• Proteins (antagonists & inhibitors, genetics)
• Proto-Oncogene Proteins c-myc (genetics)
• Receptor, Fibroblast Growth Factor, Type 3 (genetics)
• Receptors, Interleukin-6 (genetics)
• Repressor Proteins (genetics)
• STAT3 Transcription Factor (genetics)
• Signal Transduction (drug effects)
• Transcription Factors (antagonists & inhibitors, genetics)