MRP2 expression: Regulation by arsenic and effects on treatment outcomes in lung

Lung cancer is the most common cause of cancer deaths in Kentucky (KY) and the US, and KY has the highest incidence of lung cancer deaths in the US. Most lung cancers are found at an advanced stage where chemotherapy is the only viable option for treatment; responses are seen in < 50% of all patients treated with chemotherapy, are not associated with cure, and survival for most patients with advanced lung cancer is still less than one year. Clearly, novel treatment regimens and biomarkers of potential response or resistance to therapy must be identified. Arsenic is a known human carcinogen, and is found in high levels in subjects from Appalachian KY relative to non-Appalachian KY, leading to the hypotheSiS that these elevated levels of arsenic contribute to the observed higher incidence of lung cancer. We propose to determine the potential role that arsenic exposure and expression of MRP2, a protein that eliminates some cancer chemotherapeutic drugs from cells and decreases their efficacy, play in the elevated rates of lung cancer incidence and mortality in Appalachian KY. We will study normal lung cells to determine if chronic exposure to arsenic increases expression of MRP2, and thus predisposes lung cancer cells to eliminate cancer treatment drugs. We will also study lung cancer specimens that have been deposited in a tissue bank at UK to determine if they have increased expression of MRP2 in different types of non-small-cell-Iung cancer (NSCLC) cells (adenoarcinoma-vs squamous-type), and if a common genetic variant of MRP2 affects its expression in tumor cells and affects treatment outcomes. A clear understanding of the mechanism(s) by which genetic variant affects MRP2 expression, particularly in NSCLC, would justify incorporation of this genetic variant into decisions regarding 'personalized' medicine and cancer therapy, potentially increasing efficacy and decreasing toxicities of such therapy.