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Research Articles: Therapeutics, Targets, and Development

In vitro and in vivo synergy of MCP compounds with mitogen-activated protein kinase pathway– and microtubule-targeting inhibitors

¹ Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, Pennsylvania; ² Petersburg Nuclear Physics Institute, St. Petersburg, Russia; and ³ NexusPharma, Inc., Langhorne, Pennsylvania

Requests for reprints: Vladimir Khazak or Erica A. Golemis, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-214-1499; Fax: 215-214-1622. E-mail: Vladimir.Khazak{at}nexuspharm.com

Abstract

An important clinical task is to coherently integrate the use of protein-targeted drugs into preexisting therapeutic regimens, with the goal of improving treatment efficacy. Constitutive activation of Ras-dependent signaling is important in many tumors, and agents that inhibit this pathway might be useful in numerous therapeutic combinations. The MCP compounds were identified as inhibitors of Ras-Raf interactions and previously shown to inhibit multiple Ras-dependent transformation phenotypes when used as monoagents in cell culture analyses. In this study, we investigate the ability of the MCP110 compound to synergistically enhance the activity of other therapeutic agents. In both a defined K-Ras–transformed fibroblast model and in human tumor cell lines with mutationally activated Ras, MCP110 selectively synergizes with other agents targeting the mitogen-activated protein kinase pathway, and with multiple agents (paclitaxel, docetaxel, and vincristine) targeting the microtubule network. The synergistic activity of MCP110 and paclitaxel was further established by experiments showing that in Kaposi's sarcoma oncogenically transformed cell lines, cellular models for tumors treated with taxanes in the clinic and in which Raf-dependent signaling plays an important role, MCP110 synergizes with paclitaxel and limit growth. Finally, in vivo testing indicate that MCP110 is bioavailable, inhibits the growth of LXFA 629 lung and SW620 colon carcinoma cells in xenograft models, and again strongly synergizes with paclitaxel. Together, these findings indicate that MCP compounds have potential to be effective in combination with other anticancer agents. [Mol Cancer Ther 2007;6(3):898–906]

Grant support: Ben Franklin Technology Partners of Pennsylvania, RO1 CA63366 (E.A. Golemis), NIH core grant CA06927, and an appropriation from the Commonwealth of Pennsylvania (to Fox Chase Cancer Center).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Current address for S. Menon: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.

Received 9/29/06; revised 12/ 5/06; accepted 1/29/07.

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