%0 Comparative Study
%T Concomitant resistance mechanisms to multiple tyrosine kinase inhibitors in ALK-positive non-small cell lung cancer.
%A Yu Y
%A Ou Q
%A Wu X
%A Bao H
%A Ding Y
%A Shao YW
%A Lu S
%J Lung Cancer
%V 127
%N 0
%D 01 2019
%M 30642546
%F 6.081
%R 10.1016/j.lungcan.2018.11.024
%X ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next generation TKIs, have demonstrated beneficial clinical outcomes in ALK-positive non-small cell lung cancer (NSCLC). However, resistance mechanisms following multiple TKI treatments in ALK-positive NSCLC are not fully elucidated.<BR>Mutation profiles of 422 cancer-relevant genes in 52 patients with post-TKI biopsy samples were analyzed using next-generation sequencing (NGS), and compared between patients receiving crizotinib alone (n = 35) and multi-TKIs (n = 17).<BR>EML4-ALK variant 3 is the most frequent ALK variants in this cohort, followed by EML4-ALK variant 1. Half of the patients harbored ALK activating mutations upon progression on crizotinib treatment. After multi-TKIs treatment, 59% of the cases developed resistant ALK mutations, and concomitant ALK activating mutations were more commonly observed in this cohort (P = 0.031). Specifically, ALK G1269 A, L1196 M, and C1156Y substitutions were more common in crizotinib-alone samples, while ALK G1202R was significantly more enriched post-multi-TKIs (P = 0.009). Activated bypass signaling tended to be more prevalent in patients post-multi-TKIs. Furthermore, dual activation of ALK and bypass signaling was more frequently found in the multi-TKIs group (5/17, 29%) in contrast to crizotinib-alone (2/35, 6%) (P = 0.031). Additionally, concurrent TP53 mutation demonstrated significantly shorter progression-free survival (PFS) compared with TP53 wildtype in crizotinib-alone group (median PFS: 8 vs 13 months, Hazard Ratio = 1.494, P = 0.019).<BR>Concurrent ALK activating mutations and/or upregulated bypass signaling are more enriched in patients undergoing multiple ALK TKI treatments compared to crizotinib alone. Concomitant TP53 mutation correlated to unfavorable survival when receiving a single TKI crizotinib.