MP470 suppresses repair of double-strand breaks following treatment with DNA-damaging agents.

A173

MP470 is an orally bio-available multi-targeted tyrosine kinase inhibitor which hits a number of validated tumor targets. In addition, MP470 has been shown to be a potent suppressor of Rad51, a key component to the cellular repair machinery in response to DNA double strand breaks. The compound has a favorable pharmacokinetic and metabolism profile, and a large therapeutic window. Currently, MP470 is in Phase I clinical trial as a single agent; however, Phase Ib trials are projected to begin soon in combination with chemotoxic agents. In previous reports, we have shown that MP470 sensitizes cancer cells to platinum-based DNA damaging agents and to radiation therapy, presumably through the suppression of Rad51 function. In order to further understand the mechanism underlying this observed sensitization to DNA damaging agents, we have shown that MP470 inhibits the repair of DNA double strand breaks in cells following treatment with DNA damaging agents, such as etoposide, a topoisomerase II inhibitor. A549 (non-small cell lung cancer) cells were treated with a brief high dose of etoposide followed by treatment with MP470. DNA damage was monitored for two days in these cells using phospho-H2AX, a general marker for DNA double strand breaks. Phospho-H2AX levels increased significantly when etoposide treatment was followed by incubation with MP470 compared to etoposide followed by treatment with no drug. Consistent with our previous reports, these results strengthen the rationale for combining MP470 with DNA damaging agents due to the ability of MP470 to suppress the DNA repair mechanism.