Next generation sequencing reveals a novel ALK G1128A mutation resistant to crizotinib in an ALK-Rearranged NSCLC patient.

OBJECTIVE: Acquired secondary mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in ALK-rearranged non-small cell lung cancer (NSCLC) patients who are resistant to treatment with the ALK inhibitor crizotinib. We sought to uncover novel mutations that contribute to resistance in these patients.

MATERIALS AND METHODS: Following clinical diagnosis and development of crizotinib treatment resistance, tissue and ctDNA samples were obtained from the 60-year-old patient and subjected to next-generation sequencing for identification of mutations contributing to drug resistance.

RESULTS: We identified a novel acquired NSCLC ALK G1128A mutation in the ALK + NSCLC patient who progressed on crizotinib after a short partial response to the drug. This mutation, ALK G1128A, is located at the glycine loop (the P-loop) of the ALK tyrosine kinase domain. As a gain-of-function mutation, ALK G1128A increases kinase activity and transformation ability, perhaps conferring resistance to crizotinib.

CONCLUSIONS: This case further illustrates the importance of comprehensive genomic profiling of resistant tumors for tailoring treatment decisions after disease progression on crizotinib in ALK + NSCLC in the era of rapidly developing new-generation ALK inhibitors and other therapeutic strategies.