The Anaplastic Lymphoma Kinase (ALK) is a potent driver oncogene for a relevant subset of cancers, including Anaplastic Large Cell Lymphoma (ALCL), Non Small Cell Lung Cancer (NSCLC), Inflammatory Myofibroblastic tumors (IMT) and neuroblastoma. The recent development and FDA approval of first and second-generation ALK tyrosine kinase inhibitors (TKI) has revolutionized the therapeutic opportunities to treat ALK-driven cancers. In NSCLC TKI inhibitor have dramatic clinical efficacy on such tumors, but the effect is lost after a window of time of 8-10 months because of the development of TKI resistance by the tumor cells. Several molecular mechanisms of resistance have been elucidated or proposed for TKI resistant NSCLC, including ALK mutation, amplifications, or by-pass signaling by other tyrosine kinases. The elucidation of the mechanisms of resistance can dictate additional lines of therapies in relapsing patients. In contrast to NSCLC, in ALCL the clinical studies with TKI are at a very early stage and mechanisms of resistance are almost completely unknown. In this project, we aim at generating a comprehensive characterization of the molecular mechanisms that generate resistance to ALK TKI in ALCL. By hypothesis-driven or screening approaches, we will elucidate most of the resistance mechanisms and we will evaluate in pre-clinical studies additional therapeutic strategies that could be specifically used for each mechanism. Specifically, we will generate a comprehensive catalog of ALK mutations that confer resistance to TKI and their sensitivity to different ALK inhibitors. We will validate ad propose therapies for patients that become resistant by ALK amplification or PI3K upregulation. Finally we will use proteomic and genetic screens to discover novel mechanisms of resistance. Thus, our results will provide an experimental guide for the therapeutic management of lymphoma patients that develop resistance to ALK TKI.