PROJECT SUMMARY/ ABSTRACT Small cell lung cancer (SCLC) is a highly aggressive, frequently metastatic cancer that accounts for approximately 35,000 new cases annually in the United States alone. While many patients initially respond well to cisplatin-based chemotherapy, relapse within months is nearly universal. Relapsed disease is frequently resistant to chemotherapy, contributing substantially to the poor overall prognosis of SCLC patients. Decades of study have yet to produce an FDA-approved targeted therapy or a detailed understanding of chemoresistance, severely limiting treatment options for patients with relapsed disease. However, recent studies and preliminary data in this proposal suggest that overexpression of MYC family members, such as MYCL and MYCN, may play a role in SCLC chemoresistance. Therefore, detailed investigation of MYC family member overexpression in SCLC could lead to meaningful clinical advances. This proposal seeks to determine how increased levels of MYCL and MYCN contribute to chemoresistance in SCLC tumors. Aim 1 will utilize genetically engineered mouse models of SCLC, an autochthonous system, to study whether and by what mechanism MYCL or MYCN overexpression affects SCLC tumor response to cisplatin and etoposide. Aim 2 will seek to confirm and extend these findings by examining the effect of lentiviral MYCL or MYCN overexpression on response to cisplatin and etoposide in chemonaive patient derived xenograft human tumor models. These studies will deepen our understanding of the mechanisms by which SCLC develops and maintains a chemoresistant phenotype. Ultimately, the results of the experiments in this proposal can inform development of novel therapeutic agents to successfully target SCLC chemoresistance and alleviate suffering of the tens of thousands of patients with this disease.