MOLECULAR DETERMINANTS OF DRUG SENSITIVITY

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The treatment of cancer patients with chemotherapy is often empirical. Even the most active drugs produce meaningful responses in the minority of patients. As a result, many patients are exposed to and suffer the side effects of toxic medications without reaping the benefits. For example, taxanes, such as paclitaxel and docetaxel, and vinca alkaloids, such as vinorelbine, and vinblastine, are amongst the most active drugs in the treatment of common malignancies including breast, lung, and prostate. Yet, less than 50 percent of patients respond to these individual agents. Despite this, clinicians have no way of predicting who will respond and who will not. Mutations in p53 occur in approximately 50 percent of human cancers. Recent studies indicate that p53 mutations affect the sensitivity to cancer chemotherapeutic drugs. In studying the mechanism(s) underlying this observation, we found that increased expression of microtubule associated protein 4 (MAP4), which occurs when p53 is transcriptionally silent, is associated with increased sensitivity to paclitaxel and decreased sensitivity to vinca alkaloids. Using murine fibroblasts transfected with MAP4, we demonstrated that these changes in drug sensitivity were reproduced by overexpression of the MAP4 protein. MAP4 overexpression resulted in alterations in drug-induced apoptosis and cell-cycle arrest. Immunofluorescent staining of the microtubule network revealed that cells with increased MAP4 protein expression contained greater polymerized microtubules and bound more fluoresceinated paclitaxel than controls. Since MAP4 catalyzes and stabilizes the polymerization of microtubules, overexpression of this gene provides a credible mechanism to explain the sensitivity to microtubule-active drugs in the presence of mutant p53. Therefore, we propose to study the implications of these observations by analyzing the effects of p53 function on MAP4 overexpression and drug sensitivity in human cancer cell lines and following wild type p53 induction by DNA damage. We will capitalize on our findings to design more rationale uses of antimitotic drugs in combination with DNA damaging agents.