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 and, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor 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 and This combination potentiated tumor growth inhibition , 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.

Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies

“…BET inhibitors continue to garner interest as potential anticancer therapies, despite limited peer-reviewed evidence of favorable PK/PD characteristics, safety, tolerability, and efficacy. To this end, we evaluated 2 BET inhibitors, which were expected to have differentiated clinical PK profiles based on their distinct preclinical PK profiles (8,11), in 2 separate phase 1/2 studies to test the hypothesis that such differentiated PK profiles would lead to differentiated safety profiles. On the basis of previous preclinical PK studies, INCB054329 (8) was predicted to have a shorter halflife, whereas INCB057643 was predicted to have a longer half-life and a flatter PK profile.…”

“…On the basis of previous preclinical PK studies, INCB054329 (8) was predicted to have a shorter halflife, whereas INCB057643 was predicted to have a longer half-life and a flatter PK profile. However, both drugs demonstrated similar preclinical biologic and antitumor activities in vitro and in vivo (8,12,13). A BET inhibitor such as INCB054329, attaining a high peak serum concentration with a correspondingly short half-life, may have the advantage of providing a period of highlevel target inhibition, followed by a relatively extended drug holiday period that could facilitate recovery from potential toxicities, including decreased platelets.…”

“…8,12,13). Moreover, for both INCB054329 and INCB057643, inhibition of tumor growth correlated with reduction in MYC levels in xenograft models of hematologic malignancies (8,12).…”

“…In vitro and in vivo studies have demonstrated that inhibition of BRD binding downregulates key genes [e.g., MYC, BCL-2, BCL-xl, p21(C1P1/WAF1), RUNX2, and IRF4] that promote cell-cycle progression, survival, and inflammation (4,5), leading to growth inhibition in preclinical models of solid tumors and hematologic malignancies. In these studies, tumor growth associated with dysregulation of transcription factors, such as MYC, were particularly responsive to BET inhibition (6)(7)(8). On the basis of these findings, BET inhibitors are garnering interest as potential therapeutic targets for the treatment of solid tumors and/or hematologic malignancies, either as a monotherapy or in combination with standard-of-care (SOC) and/or novel anticancer agents.…”

“…Early clinical experience with BET inhibitors revealed challenges in balancing optimal target inhibition with the management of treatment-associated toxicities (9,10); of note, the pharmacokinetic (PK) and pharmacodynamic (PD) profile for BET inhibitors that provides an optimal therapeutic index has not been determined. INCB054329 (8) and INCB057643 are structurally distinct smallmolecule BET inhibitors, with differentiated PK profiles based on experimental PK data from preclinical studies: INCB054329 with higher clearance and a shorter half-life, and INCB057643 with lower clearance and a correspondingly longer half-life (11). In preclinical in vitro and in vivo studies, both drugs showed similar PD and antitumor activities, and elicited antiproliferative activities against a panel of hematologic and solid tumor cancer cell lines.…”