Molecular mechanisms of acquired drug resistance in small cell lung cancer

Small cell lung cancer (SCLC) is a common, aggressive, and exceptionally lethal type of lung cancer that is not typically discovered or diagnosed until it has already spread throughout the body. Newly diagnosed SCLC is remarkably sensitive to combination therapy with a combination of two drugs, cisplatin and etoposide, even in patients with extensive-stage disease. While many tumors respond to therapy, shrinking significantly in bulk, this treatment is never curative – when these tumors return, they are generally quite resistant to further therapy. Extensive-stage SCLC is uniformly fatal; less than 1% of patients will be alive five years after diagnosis.  Remarkably little is known about how or why these tumors become resistant to this therapy. Defining the basis of acquired chemotherapy resistance in SCLC could have clear and important ramifications for clinical management of this disease. Targeting the key determinants of acquired chemoresistance could be integrated into first-line treatment, and/or could drive rational targeted therapeutic studies for recurrent disease. There are now multiple technical approaches that could comprehensively define the genomic and epigenetic changes that drive acquired resistance in SCLC.  This research will use two parallel approaches to analyzing acquired resistance in SCLC: studying resistance in patient samples and studying resistance in patient tumors grown in mice.