Next-Generation Sequencing Reveals a Novel NSCLC ALK F1174V Mutation and Confirms ALK G1202R Mutation Confers High-Level Resistance to Alectinib (CH5424802/RO5424802) in ALK-Rearranged NSCLC Patients Who Progressed on Crizotinib

作者：Ou Sai Hong Ignatius^*; Azada Michele; Hsiang David J; Herman June M; Kain Tatiana S; Siwak Tapp Christina; Casey Cameron; He Jie; Ali Siraj M; Klempner Samuel J; Miller Vincent A

来源：Journal of Thoracic Oncology, 2014, 9(4): 549-553.

DOI：10.1097/JTO.0000000000000094

• ALK F1174V
• ALK G1202R
• Crizotinib resistance
• Alectinib
• ALK-rearranged NSCLC
• Next-generation sequencing

Acquired secondary mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients who developed disease progression while on crizotinib treatment. Here, we identified a novel secondary acquired NSCLC ALK F1174V mutation by comprehensive next-generation sequencing in one ALK+ NSCLC patient who progressed on crizotinib after a prolonged partial response to crizotinib. In a second case, we identified a secondary acquired ALK G1202R, which also confers resistance to alectinib (CH5424802/RO5424802), a second-generation ALK inhibitor that can inhibit ALK gatekeeper L1196M mutation in vitro. ALK G1202R is located at the solvent front of the ALK kinase domain and exhibits a high level of resistance to all other ALK inhibitors currently in clinical development in vitro. Comprehensive genomic profiling of resistant tumor is increasingly important in tailoring treatment decisions after disease progression on crizotinib in ALK+ NSCLC given the promise of second-generation ALK inhibitors and other therapeutic strategies.

• 出版日期2014-4