![]() Active Ras promotes tumor growth through its ability to activate multiple downstream effector signaling pathways that promote cell proliferation, survival, migration, and angiogenesis (reviewed in refs. In some tumors, Ras is directly activated by mutation, whereas in others the constitutive signaling of upstream regulatory factors, such as the epidermal growth factor receptor, promote deregulated activation of wild-type Ras ( 2). Īctivation of the Ras oncoprotein is a critical element in many different cancers, including pancreatic, breast, and others (reviewed in ref. Together, these findings indicate that MCP compounds have potential to be effective in combination with other anticancer agents. 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. 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. 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. In this study, we investigate the ability of the MCP110 compound to synergistically enhance the activity of other therapeutic agents. 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. Constitutive activation of Ras-dependent signaling is important in many tumors, and agents that inhibit this pathway might be useful in numerous therapeutic combinations. 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. ![]()
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