Abstract
Targeted therapy with tyrosine kinase inhibitors (TKI) provides survival benefits to a majority of patients with non-small cell lung cancer (NSCLC). However, resistance to TKI almost always develops after treatment. Although genetic and epigenetic alterations have each been shown to drive resistance to TKI in cell line models, clinical evidence for their contribution in the acquisition of resistance remains limited. Here, we employed liquid biopsy for simultaneous analysis of genetic and epigenetic changes in 122 Vietnamese NSCLC patients undergoing TKI therapy and displaying acquired resistance. We detected multiple profiles of resistance mutations in 51 patients (41.8%). Of those, genetic alterations in EGFR, particularly EGFR amplification (n = 6), showed pronounced genome instability and genome-wide hypomethylation. Interestingly, the level of hypomethylation was associated with the duration of response to TKI treatment. We also detected hypermethylation in regulatory regions of Homeobox genes which are known to be involved in tumor differentiation. In contrast, such changes were not observed in cases with MET (n = 4) and HER2 (n = 4) amplification. Thus, our study showed that liquid biopsy could provide important insights into the heterogeneity of TKI resistance mechanisms in NSCLC patients, providing essential information for prediction of resistance and selection of subsequent treatment.
Highlights
Targeted therapy with tyrosine kinase inhibitors (TKI) provides survival benefits to a majority of patients with non-small cell lung cancer (NSCLC)
We examined the application of plasma cell free DNA to simultaneously profile genetic and methylation landscapes in 122 Vietnamese NSCLC patients who developed acquired resistance to TKI drugs
Liquid biopsy from all 122 patients were sampled at the time of disease progression after achieving partial or stable disease (> 3 months) or at least 6 months post TKI treatment, satisfying the criteria of acquired resistance proposed by RECIST (Response Evaluation Criteria in Solid Tumours) or WHO15,16
Summary
Targeted therapy with tyrosine kinase inhibitors (TKI) provides survival benefits to a majority of patients with non-small cell lung cancer (NSCLC). Clinical studies have shown that patients carrying sensitizing EGFR mutations displayed prolonged progression-free survival upon receiving first generation tyrosine kinase inhibitors (TKI) including erlotinib and gefitinib[3,4,5] or the second generation TKI afatinib[6,7]. Such TKI drugs were shown to either reversibly (first generation TKI, 1G TKI) or irreversibly (second generation TKI, 2G TKI) bind to the ATP binding site of the tyrosine kinase domain of EGFR, thereby inactivate its activity[8]. Findings from such models may under-represent the complexity of resistance mechanisms in NSCLC patients
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