Abstract 1885: Selective Polo-like Kinase 1 (PLK1) inhibitor PCM-075 is highly active alone and shows synergy when combined with FLT3 inhibitors in models of acute myeloid leukemia (AML)

Abstract

Abstract First generation FLT3 inhibitors have been useful in treating AML (sorafenib, midostaurin). Second generation inhibitors with more selectivity are currently in P3 trials in AML (quizartinib, gilteritinib). Despite the advances, resistance to FLT3 inhibitors and disease progression while on FLT3 inhibitors remains an important problem for patient care. We analyzed the activity of a highly-selective PLK1 inhibitor, PCM-075 (formerly NMS-1286937), in models of acute myeloid leukemia (AML) alone and in combination with various chemotherapies and targeted therapeutics including FLT3 inhibitors. PCM-075 is a potent, highly-selective adenosine triphosphate competitive inhibitor of PLK1, a serine/threonine kinase, which is over-expressed in hematologic malignancies and solid tumors such as AML, breast, prostate, ovarian, lung, gastric and colon. PCM-075 is highly active in blocking proliferation and inducing G2/M arrest in multiple AML cell lines. In a therapeutic model, PCM-075 was capable of inducing significant tumor growth inhibition (TGI)1, and increasing survival in an in vivo disseminated leukemia model (AML-NS8 Cells)2. Orally administered PCM-075 is currently in development for multiple tumor types and is in clinical trials for the treatment of AML (NCT03303339). Synergistic interactions between Quizartinib, other FLT3 inhibitors and PCM-075 were examined in cell culture models. In vivo, combination studies in an AML FLT3 mutant 21 day treatment xenograft model (MV4-11) revealed synergistic interactions between Quizartinib and PCM-075. PCM-075 (dosed orally 30 mg/kg, QD for days 1-10 and 12 -21) in combination with Quizartinib (1 mg/kg, QD for 21 days) resulted in 97.3% (96.2-98.4) TGI, compared to 77.9% (70.0-85.8) with Quizartinib and 80.2% (70.4-90.0) with PCM-075 as monotherapy. Body weight in treated mice remained within 20% of controls. To better understand the mechanism of the synergistic activity of PCM-075, we have conducted in vitro RNA-based profiling studies examining the combination of PCM-075 with FLT3 inhibitors for impact on specific gene pathways in AML cell lines and this will be presented. Combination therapy is the mainstay of current oncology treatment regimens and these results suggest that combining PCM-075 with FLT3 inhibitors could be useful in the treatment of AML and a potential next step for patients developing resistance to FLT3 inhibitors. 1 Mol Cancer Ther. 2012 Apr;11(4):1006-162 PLoS One. 2013;8(3):e58424 Citation Format: Karena Kosco, Maya Ridinger, Penn Whitley, Peter Croucher, Jeffrey N. Miner, Mark Erlander. Selective Polo-like Kinase 1 (PLK1) inhibitor PCM-075 is highly active alone and shows synergy when combined with FLT3 inhibitors in models of acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1885.