Antitumor Activity Of Chk1 Inhibitor Ly2606368 As A Single Agent In Sw1990 Human Pancreas Orthotopic Tumor Model

ChK1 is a key kinase in the DNA damage response signaling network, including cell cycle checkpoints, DNA repair, apoptosis and transcription, thus emerging as an attractive target in anti-cancer therapy. LY2606368, a potent and selective ATP competitive inhibitor of the Chk1 protein kinase, is currently in clinical development. LY2606368 has been reported to inhibit Chk1 auto-phosphorylation activated by DNA damaging agents, and induce phosphorylation of H2AX, a DNA damage maker in multiple cancer cell lines in vitro. In addition, LY2606368 has demonstrated potent single agent activity and potentiates the anti-tumor activity of DNA damaging agents in vivo. Pancreatic cancer is one of the least curable cancers, with an approximate 5% overall 5-year survival for all patients. In the current study, we evaluated the efficacy of LY2606368 (as its methanesulfonate salt, hydrate; LY2606368.MeSO3H.H2O = LY2940930) in pancreatic cancer cell lines in vitro and xenograft tumors (including subcutaneous and orthotopic models) in vivo. LY2606368 alone significantly inhibited the cell proliferation in a variety of pancreatic cell lines (SW1990, SU86.86, Bx-PC3, AsPC-1, CFPAC-1, Capan-2, HPAF-II) with SW1990 being the most sensitive (IC50=1.5 nM). In SW1990 subcutaneous xenograft model, LY2606368 showed substantial dose-dependent inhibition of tumor growth. In SW1990 pancreas orthotopic model, which represents the local and metastatic growth pattern seen in pancreas cancer patients, LY2606368 treatment resulted in over 92% inhibition of primary tumor growth as well as 100% inhibition of metastasis to lymph node, spleen and intestine. The anti-tumor effect of LY2606368 treatment was further demonstrated in comparing with gemcitabine (the standard of care for pancreas cancer patient) in SW1990 orthotopic model. The anti-tumor and/or anti-metastasis mechanism of LY2606368 was also investigated, including phosphorylation of H2AX, cell proliferation, cell survival, and soft agar anchorage-independent growth. Together, our findings demonstrate the therapeutic potential of LY2606368 as a single agent in the treatment of pancreatic cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1776. doi:1538-7445.AM2012-1776