Small Cell Lung Cancer (SCLC) accounts for 15% of all lung cancers (approximately 330,000 people/year worldwide), usually presenting with metastases at diagnosis and short response to treatment. Since no major advances have been achieved in SCLC treatment in the past decades, it is now categorized as a “recalcitrant” cancer. SCLC development usually starts in a chemo-sensitive and neuroendocrine (NE) state, which transitions to a non-neuroendocrine (non-NE) state over time, and less responsive to chemotherapy. Although studies focusing on the phenotype switching of SCLC cell states found some key regulators, our knowledge is still very limited. Our work will focus on interrogating how the epigenome of SCLC is regulated during the switching of neuroendocrine states. To understand this process, we will follow genome wide changes of histone modifications, chromatin accessibility, genome structure and transcription. In addition, we will characterize oncogenic amplification of cell cycle regulating MYC paralogues (MYC, MYCL and MYCN), and their association to neuroendocrine status and amplification mechanism. These studies will help us identify potential drug response targets to help improve therapy of SCLC.