Overexpression of the adaptor protein CRKL as a mechanism of acquired resistance to Crizotinib in ALK-positive NSCLC

摘要: Background: The fusion of the anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a known oncogenic driver in a subset of non-small cell lung cancer (NSCLC). An ALK/ROS1/MET kinase inhibitor, Crizotinib, was approved in 2011 for the treatment of patients with metastatic ALK+ NSCLC. Despite the dramatic clinical effects of Crizotinib in EML4-ALK positive NSCLC, vast majority of patients subsequently acquire resistance and new therapeutic strategies are needed.Methods and Results: We performed a kinase (n=597) open reading frame screen to identify kinases and phosphoproteins capable of circumventing ALK inhibition in H3122 cell line sensitive to the ALK kinase inhibitor TAE684. The top hit of the screen imparting resistance to TAE684 was the adaptor phospho-protein CRK-like (CRKL), a known substrate of BCR-ABL. To validate our screen, we …