Novel resistance mechanisms including L1196Q, P1094H, and R1248_D1249insertion in three patients with non-small-cell lung cancer following ALK tyrosine kinase inhibitor treatment.

Abstract Purpose The purpose of this study is to clarify the details of the anaplastic lymphoma receptor (ALK) tyrosine kinase inhibitor (TKI) resistance mechanism in re-biopsy cases and to predict novel resistance gene alterations using Molecular dynamics (MD) simulation. Methods A total of 21 ALK-positive non-small-cell lung cancer (NSCLC) patients who underwent a re-biopsy after ALK TKI failure were included to this analysis. ALK fluorescence in situ hybridization and reverse transcription polymerase chain reaction were performed with paired initial and re-biopsy tumor specimens. Results Nine patients had no known ALK resistance mechanisms. Four had ALK amplification. L1196M, I1171N, and G1269A, mutations which are known to indicate resistance to ALK-TKIs, were detected in one patient each. Small cell carcinoma and sarcomatoid transition were recognized in one case each. L1196Q, P1094H, and exon24 insertion 76bp were detected after the second-generation ALK-TKIs. Conclusions The combination of a genetic analysis and computational simulation model may make a prediction of resistance mechanisms for overcoming ALK-TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.