DNA damage repair deficiency is associated with early resistance to crizotinib: Whole-genome analysis in non-small cell lung cancer patients with ALK-fusion

Abstract

Background: ALK-tyrosine kinase inhibitor (TKI) is associated with a favarable survival benefit in ALK-fusion patients in advanced non-small cell lung cancer (NSCLC). However, almost 20% patients with TKI early resistance (progression-free survival is shorter than six months while treated by either crizotinib or second-line TKIs), show a poor survival with no more than one year. The mechanisms of early resistance to TKIs are unknown. Reliable biomarkers are required to predict the response to ALK-TKIs, especially in the early resistance. So we investigated genomic variations associated with responses to crizotinib in advanced NSCLC patients with ALK-fusion. Methods: Advanced NSCLC primary tumor samples with ALK-fusion from 5 extreme poor and 5 extreme strong responders to crizotinib were subjected to whole-genome analysis. And we found 44 genomic variant sites with poor response through gene based pathway enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then we randomly assigned 17 advanced NSCLC patients' sample with ALKfusion to validate the candidate variant sites using small sequence capture panel. Genomic data of>0.2 gigabases/sample was generated at average of 828 sequencing depth which covering 44 relative genes. Results: In total, 774 genomic variations were matched to crizotinib responses in clinical data; which were located within regions for DNA repaired, mitochondrial apoptosis and tumor angiogenesis-target genes. From them, 4 DNA damage repair (DDR)-related gene variations (TP53, MLH1, XPA, and MSH2) were associated with early resistance to crizotinib in ALK-fusion NSCLC patients, from which 5 variants were within the coding regions and 4 identified as non-synonymous single-nucleotide variants. Validation genotyping confirmed sequencing results and revealed patients genotype for rs28934575 in TP53 showed extreme shorter PFS (P<0.002) to crizotinib and poor survival, while the median PFS was 3 months (range, 2-5 months, 95% CI:2.2-3.8 months). And these patients survived no more than 12 months. Conclusions: Thus, DDR deficiency may contribute to the early resistance to crizotinib in ALK-fusion patients.