Title: Identification of a novel T1151K ALK mutation in a patient with ALK -rearranged NSCLC with prior exposure to crizotinib and ceritinib
Abstract: Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) derive significant clinic benefit from treatment with ALK inhibitors. Crizotinib was the first approved tyrosine kinase inhibitor (TKI) for this distinct molecular subset of NSCLC. Disease progression on TKI inevitably arises secondary to diverse resistance mechanisms among which emergence of secondary ALK mutations is one of many ways in which tumor cells have adapted to survive. Therefore there is a clinical imperative to identify acquired ALK mutations via repeat tissue biopsy if clinically feasible. If such is present, switching to a different TKI with known clinical activities against the emergent resistance mutation (s) may pose a viable treatment option. Here we report for the first time a novel ALK T1151K mutation in a patient with metastatic ALK-rearranged NSCLC who progressed on crizotinib and then ceritinib. The co-crystal structure of ceritinib/ALK demonstrates a strong interaction between ceritinib and the P-loop which is facilitated by T1151 on the β3 sheet, a feature not present in the alectinib/ALK or lorlatinib/ALK co-crystal structure. It is predicated that the T1151K mutation weakens these interactions leading to drug resistance, or causes conformational changes of the ALK catalytic domain resulting in higher affinity for ATP and therefore diminished inhibitor binding. We conclude that the T1151K ALK mutation confers resistance to ceritinib, which may be rescued by alectinib or lorlatinib as evidenced by this clinical narrative.