ALK and neoplasm: To overcome the known limitations in biopsy specimens with regard to tumor quantity and quality, recent studies have used patient-derived cell lines and xenograft models, which have led to the identification of two major classes of ALK TKI resistance mechanisms [10]: on one hand ALK-dependent, “on-target” mechanisms, which include ALK secondary resistance mutations or amplification, where the tumor cell dependency on ALK signaling persists.