Secondary mutations in ALK and resistance to ALK kinase inhibitors

摘要: Background: The anaplastic lymphoma kinase (ALK) inhibitor crizotinib is clinically effective in cancer patients whose tumors harbor ALK translocations. However, drug resistance will ultimately develop in most if not all patients. We studied drug resistance mechanisms using both in vitro models and analyses from tumors of patients that had developed crizotinib resistance. Methods and Results: We identified a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harbouring a RANBP2-ALK translocation who progressed while crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib mediated downregulation of ALK signaling and blocks …