In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 5414-5414
Abstract:
The PIM family of serine-threonine protein kinases (PIM1, PIM2 and PIM3) mediates responses to cytokines and growth factors and drives cell proliferation and survival in a number of hematologic malignancies. Overexpression of PIM kinases in these malignancies, including multiple myeloma (MM), has been associated with poor overall survival. Given the overlapping functions of these kinases, the ability of one family member to compensate for the loss of another as well as the relatively benign phenotype of mice deficient in all three PIM isoforms, discovery of pan-PIM kinase inhibitors is warranted. The in vitro and in vivo activity of the pan-PIM kinase inhibitor, INCB53914, was determined in MM cell lines. The antiproliferative potencies for INCB053914 were & lt;200 nM in the majority of MM cell lines tested. INCB053914 potently suppressed the phosphorylation of multiple PIM substrates in MM cell lines, however in contrast, a PIM2-sparing compound, INCB050646, was unable to impact signaling in the KMS12 MM cell line, suggesting the importance of the PIM2 isoform in myeloma growth and survival. An assay was established to measure the inhibition of the phosphorylation of the PIM substrate, BAD, in KMS12 cells when spiked into whole blood (WB) to assess the shift in compound potency due to protein binding. The IC50 for INCB053914 in this assay was similar to its potency in suppressing BAD phosphorylation in KMS12 tumors in vivo. Dose dependent tumor growth inhibition (TGI) was seen in mice bearing KMS12 tumors, with maximal TGI achieved with 24 hours of KMS12 WB IC50 coverage. Similar data were obtained in a second MM model, OPM2. To understand the impact of inhibiting the PIM pathway in combination with other pathways dysregulated in hematological malignancies, an unbiased in vitro screen was performed and the potential synergy of INCB053914 in combination with 65 cytotoxic or targeted agents was determined. This screen identified several agents active against the PI3K pathway or which impacted cell cycle progression. In addition, the combinatorial activity of selected targeted agents hypothesized to exhibit significant interactions with the PIM pathway was assessed in vivo. Since PIM family members are STAT regulated genes, enhanced activity may be expected upon combined PIM and JAK inhibition. In fact, synergistic activity was seen with this combination in the INA6 multiple myeloma model, and pharmacodynamic analyses revealed enhanced suppression of both pBAD and c-myc levels in tumors from treated mice. Additionally, c-myc levels are regulated both by PIM and the BET family member, BRD4. The expected synergistic efficacy of PIM and BET inhibitors was also observed in the KMS12 model, again with enhanced reduction in pBAD and c-myc levels in the tumors of treated mice. Taken together, these data support the utility of PIM inhibition in MM patients, both as monotherapy and in combination with other targeted agents. Citation Format: Holly Koblish, Niu Shin, Leslie Hall, Xiaoming Wen, Sybil O'Connor, Valerie Dostalik, Qian Wang, Kathy Wang, Maryanne Covington, Cindy Marando, Kevin Bowman, Jason Boer, Krista Burke, 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 multiple myeloma. [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 5414. doi:10.1158/1538-7445.AM2015-5414
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-5414
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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