Abstract 5416: Activity of the pan-PIM kinase inhibitor INCB053914 in models of acute myelogenous leukemia

Abstract

Abstract The PIM family of serine-threonine protein kinases (PIM1, PIM2 and PIM3) was initially identified as preferential integration sites of the Moloney murine leukemia virus in Eμ-myc mice, resulting in perinatal lymphomagenesis. Molecular characterization has revealed that PIM kinases drive cell proliferation and survival in a number of hematological malignancies beyond lymphomas by mediating responses to cytokines, growth factors and cellular stress. Overexpression of various PIM kinase family members in these malignancies has been associated with poor overall survival and with resistance to chemotherapeutic agents. Therefore, development of a pan-PIM inhibitor may be useful in the treatment of hematological malignancies, both as a single agent and in combination with chemotherapy or targeted agents. The in vitro and in vivo activity of INCB053914, a pan-PIM kinase inhibitor, was determined in a panel of acute myelogenous leukemia (AML) cell lines. Greater than half of all AML cell lines tested were sensitive to single agent INCB053914, with anti-proliferative IC50 potencies <100 nM. Consistent with recent findings, the majority of these sensitive cell lines expressed higher levels of CD25, which is co-regulated with PIM through the JAK/STAT signaling pathway and which may serve as a biomarker for PIM sensitivity in AML. INCB053914 suppressed the phosphorylation of multiple PIM kinase substrates and, in a compensatory manner, increased PIM kinase expression in both cell lines and primary AML patient samples. The potency of INCB053914 to suppress BAD phosphorylation in vivo in MOLM16 tumors is consistent with its potency in blocking BAD phosphorylation in MOLM16 cells spiked into human whole blood in vitro. Dose dependent tumor growth inhibition (TGI) was seen in mice bearing MOLM16 tumors, with maximal TGI achieved with 12-20 hours of MOLM16 WB IC50 coverage. Synergistic activity was seen in vivo in the KG1 model when INCB053914 was administered with cytarabine, a standard of care therapy for AML. Further studies were undertaken to assess the potential for combined PIM inhibition with other targeted agents. Because the PIM kinases have been shown to regulate c-myc expression levels, agents whose activity has been shown to be influenced by c-myc levels or to regulate c-myc expression were examined. The combination of INCB53914 with the pan-BET inhibitor INCB54329 in MOLM16 xenografts synergistically decreased pBAD and c-myc levels in tumors, resulting in enhanced efficacy. Synergy was also seen when INCB53914 was combined with the pan-FGFR inhibitor INCB54828 in KG1 xenografts harboring the FOP-FGFR1 translocation, suggesting that this combination might be useful in this rare patient population as well as other diseases driven by oncogenic FGFR activation. Taken together, these data support the utility of PIM inhibition in AML patients as monotherapy and in combination with other targeted agents. Citation Format: Holly Koblish, Niu Shin, Leslie Hall, Sybil O'Connor, Qian Wang, Kathy Wang, Lynn Leffet, Maryanne Covington, Krista Burke, Jason Boer, Kevin Bowman, Ke Zhang, Hao Feng, Chu-Biao Xue, Yun-Long Li, Wenqing Yao, Reid Huber, Kris Vaddi, Peggy Scherle. Activity of the pan-PIM kinase inhibitor INCB053914 in models of acute myelogenous leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5416. doi:10.1158/1538-7445.AM2015-5416