Date Published: June 21, 2018
Publisher: Public Library of Science
Author(s): Holly Koblish, Yun-long Li, Niu Shin, Leslie Hall, Qian Wang, Kathy Wang, Maryanne Covington, Cindy Marando, Kevin Bowman, Jason Boer, Krista Burke, Richard Wynn, Alex Margulis, Gary W. Reuther, Que T. Lambert, Valerie Dostalik Roman, Ke Zhang, Hao Feng, Chu-Biao Xue, Sharon Diamond, Greg Hollis, Swamy Yeleswaram, Wenqing Yao, Reid Huber, Kris Vaddi, Peggy Scherle, Kevin D. Bunting.
The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine protein kinases are overexpressed in many hematologic and solid tumor malignancies and play central roles in intracellular signaling networks important in tumorigenesis, including the Janus kinase–signal transducer and activator of transcription (JAK/STAT) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. The three PIM kinase isozymes (PIM1, PIM2, and PIM3) share similar downstream substrates with other key oncogenic kinases and have differing but mutually compensatory functions across tumors. This supports the therapeutic potential of pan-PIM kinase inhibitors, especially in combination with other anticancer agents chosen based on their role in overlapping signaling networks. Reported here is a preclinical characterization of INCB053914, a novel, potent, and selective adenosine triphosphate-competitive pan-PIM kinase inhibitor. In vitro, INCB053914 inhibited proliferation and the phosphorylation of downstream substrates in cell lines from multiple hematologic malignancies. Effects were confirmed in primary bone marrow blasts from patients with acute myeloid leukemia treated ex vivo and in blood samples from patients receiving INCB053914 in an ongoing phase 1 dose-escalation study. In vivo, single-agent INCB053914 inhibited Bcl-2–associated death promoter protein phosphorylation and dose-dependently inhibited tumor growth in acute myeloid leukemia and multiple myeloma xenografts. Additive or synergistic inhibition of tumor growth was observed when INCB053914 was combined with selective PI3Kδ inhibition, selective JAK1 or JAK1/2 inhibition, or cytarabine. Based on these data, pan-PIM kinase inhibitors, including INCB053914, may have therapeutic utility in hematologic malignancies when combined with other inhibitors of oncogenic kinases or standard chemotherapeutics.
The Proviral Integration site of Moloney murine leukemia virus (PIM) family of intracellular serine/threonine kinases consists of three highly homologous isozymes (PIM1, PIM2, and PIM3), each of which has been implicated in many hematologic and solid tumor malignancies . PIM isozyme expression is elevated by cytokines and growth factors (eg, interleukin-6, interleukin-10, and granulocyte-macrophage colony-stimulating factor) that mediate signaling networks, which are themselves dysregulated in a wide range of cancers [1, 2]. For example, many of these cytokines signal through the Janus kinase (JAK and signal transducer and activator of transcription (STAT) pathway, which is both critical for normal hematopoiesis and associated with myeloproliferative neoplasms (MPNs) .
INCB053914 (N-((R)-4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide phosphate), INCB050465, itacitinib (formerly INCB039110), and ruxolitinib (formerly INCB018424) were synthesized at Incyte Corporation (Wilmington, Delaware). Cytarabine was from Hanna Pharmaceutical Supply (Wilmington, Delaware). All tumor cell lines (MM, n = 11; AML, n = 15; B-cell malignancies, n = 13 [DLBCL, n = 9; MCL, n = 4]; T-cell acute lymphoblastic leukemia [T-ALL], n = 4; Hodgkin lymphoma, n = 1) were from ATCC® (Rockville, Maryland) or DSMZ (Braunschweig, Germany), except for INA-6 (MM) cells, which were kindly provided by Dr. R. Burger (University Hospital Schleswig-Holstein, Kiel, Germany). Cultures were maintained according to supplier recommendations. Data plots and statistics were generated using GraphPad Prism version 5.0 (GraphPad Software, La Jolla, California).
PIM kinases function in cells as integrators of several signaling networks that overlap with those that can be targeted by other anticancer agents and that share common downstream substrates [1, 2]. For example, signaling networks mediated by PIM kinases overlap substantially with the PI3K/AKT/mTORC1 pathway [1, 2, 9]; PIM kinases and mTORC1 both block the anti-apoptotic function of BAD . In addition, both PIM2 and mTORC1 phosphorylate 4E-BP1 via parallel signaling pathways, which then upregulates cap-dependent protein translation [1, 17]. We therefore hypothesized that along with potential single-agent activity, there also could be synergy between the in vitro and in vivo antitumor effects of INCB053914 and those of other rationally chosen anticancer agents.