A Study Of Early Resistance Of Crizotinib And Prognosis In Advanced Non-small Cell Lung Cancer Patients With ALK-fusion

Background & AimsThe usage of tyrosine kinase inhibitor(TKI)has brought long-term survival benefits to patients with advanced non-small cell lung cancer(NSCLC)with ALK-fusion.However,about 20% patients will develop early TKI resistance(progression-free survival time ≤ 6.0 months)when receiving crizotinib or second-line TKIs,and exhibit an overall survival of less than one year.At present,mechanisms of early TKIs resistance are still largely unknown,and reliable biomarkers are needed to predict the response of patients with early drug resistance to ALK-TKIs.In this study,we investigated molecular marker associated with early drug resistance to crizotiniband prognosis in patients with advanced NSCLC patients with ALK-fusion.Materials & methods:Advanced NSCLC primary tumor samples with ALK-fusion from 5 extreme poor(progression-free survival time ≤ 3.0 months)and 5 extreme strong(progression-free survival time ≥ 24.0 months)responders to crizotinib were subjected to whole exome sequencing(WES).Bioinformatics analysis was used to screen mutation genes related to early drug resistance and prognosis of crizotinib,and furthermore,enrichment analysis of pathways was performed in the Kyoto Encyclopedia of Genes and Genomes(KEGG).Next,we personalized the probes covering the related mutant genes,and used the target sequence capture method to verify the sequencing of the primary tumor tissue samples of 19 crizotinib-treated NSCLC patients.Finally,combined with clinical data and bioinformatics analysis outcomes,survival analysis was performed.ResultsWe performed WES on the tumor tissue samples of 5 lung cancer patients with extremely poor crizotinib treatment and 5 cases with excellent good crizotinib treatment,the average sequencing depth of each sample is 828×,and the sequencing data of each sample is greater than 0.2G.A total of 264 somatic mutations were detected in 10 samples,and the number of somatic mutations was higher in the group with extremely poor therapeutic effect(P < 0.001).We also found that there were more co-mutation genes and higher tumor mutation burden(TMB)in the group with extremely poor therapeutic effect(P = 0.002).We identified 38 early drug resistance or prognosis-related gene mutations that are majorly enriched in mitochondrial apoptosis,tumor angiogenesis,DNA repair and platinum-resistance pathways.The mutations of TP53 and DDR-related genes MLH1,XPA and MSH2 may be related to the early resistance of crizotinib.A combined analysis of 29 patients revealed that NSCLC patients with ALK fusion gene carrying TP53 G245 S mutation correlated with poor progression-free survival and prognosis(P < 0.05).ConclusionOur study demonstrated that co-mutations of TP53 G245 S and DNA repair-related genes may be associated with early crizotinib resistance and poor prognosis in advanced NSCLC patients with ALK-fusion gene mutation,however,this requires further investigation in prospective clinical trials.And these patients may benefit from immunotherapy or combined immunotherapy.