Abstract 1823: Characterization of the anti-angiogenic properties of merestinib (LY2801653), an oncokinase inhibitor
Authors: Bodenmiller Diane M. , Stewart Julie A. , Evans Glenn F. , Peek Victoria L. , Stephens Jennifer R. , Lin Xi , Iyer Seema , Falcon Beverly L. , Chintharlapalli Sudhakar , Yan Sau-Chi Betty , Fischl Anthony S. 
Published: July 2017

Merestinib (LY2801653) is an orally bioavailable small molecule inhibitor of several oncokinases, including MET, AXL, DDR1/2, MERTK, ROS1, Tie2 (aka TEK), and MKNK1/2. Merestinib has been extensively characterized in a wide range of preclinical tumor xenograft models and shown to potently inhibit MET driven and non-MET driven tumor growth. In addition to its direct antitumor activity, merestinib inhibits angiogenesis and induces a tumor vessel normalization phenotype in xenograft tumors1. While MET signaling is important for angiogenesis, the effect of merestinib on angiogenesis is likely not exclusively driven by MET inhibition. In co-culture angiogenesis assays, merestinib inhibited VEGF-dependent and VEGF-independent endothelial cell cord formation2,3 and sprouting4 with potencies in the low nM range (3-30 nM). In contrast, the MET-specific kinase inhibitor, PF04217903, only weakly inhibited cord formation and endothelial sprouting. In an established in vivo matrigel co-implant vasculogenesis model where VEGFR2 or MET selective inhibition had minimal effect, merestinib decreased vascular density by 69%. In addition, while MET antibody emibetuzumab (human anti-MET antibody) plus ramucirumab (human anti-VEGFR2 antibody) decreased vascular density by 64%, merestinib plus ramucirumab decreased it by 92%. In a mouse adenovirus-driven VEGF-A ear angiogenesis model5, treatment with DC101, a mouse anti-VEGFR2 antibody, or merestinib inhibited angiogenesis; however the combination of DC101 and merestinib appeared to inhibit it even more. Finally, in the MKN45 gastric tumor xenograft model, merestinib (T/C = 4.8%) and DC101 (T/C = 15.3%) each significantly inhibited tumor growth alone and the combination resulted in 27.6% tumor regression and was significantly better than either single agent alone. Together, these studies indicate that merestinib has greater effects on angiogenesis than selective MET inhibition and its actions are not dependent on VEGFR2. In addition, while in vitro studies show reductions in VEGFR2 phosphorylation with high concentration of merestinib, treatment with merestinib did not inhibit VEGF dependent phosphorylation of VEGFR2 in mouse lung tissue at clinically relevant exposures. These data suggest that the anti-angiogenic activity of merestinib includes activities of other kinases targeted by merestinib. These data provide rationale and support for the clinical evaluation of combination of merestinib with ramucirumab (NCT02745769). 1-Yan et. al. Invest New Drugs. 2013;31:833-844, 2- Falcon et. al. J Hematol Oncol. 2013;6:31, 3- Falcon et. al. PLoS ONE. 2014;9:e106901, 4- Nakatsu et. al. Methods Enzymol. 2008;433:65-82, 5- Nagy et. al. Methods Enzymol. 2008;444:43-64.

Citation Format: Diane M. Bodenmiller, Julie A. Stewart, Glenn F. Evans, Victoria L. Peek, Jennifer R. Stephens, Xi Lin, Seema Iyer, Beverly L. Falcon, Sudhakar Chintharlapalli, Sau-Chi Betty Yan, Anthony S. Fischl. Characterization of the anti-angiogenic properties of merestinib (LY2801653), an oncokinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1823. doi:10.1158/1538-7445.AM2017-1823