Identification Of Genetic Variations Associated With Drug Resistance In Non-small-cell Lung Cancer Patients Undergoing Systemic Treatment

BackgroundNon-small cell lung cancer(NSCLC)is characterized by relatively rapid response to systemic treatments yet inevitable resistance and predisposed to distant metastasis.We thus aimed at performing sequencing analysis to determine genomic events and underlying mechanisms concerning drug resistance in NSCLC.MethodsWe performed targeted sequencing of 40 medication-relevant genes on plasma samples from 98 NSCLC patients and analyzed impact of genetic alterations on clinical presentation as well as response to systemic treatments.Profiling of multi-omics data from 1024 NSCLC tissues in public datasets was carried out for comparison and validation of identified molecular events implicated in resistance.ResultsA genetic association of CYP2D6 deletion with drug resistance was identified through circulating tumor DNA(ct DNA)profiling and response assessment.FCGR3 A amplification was potentially involved in resistance to EGFR inhibitors.We further verified our findings in tissue samples and focused on potential resistance mechanisms,which uncovered that depleted CYP2D6 affected a set of genes involved in EMT,oncogenic signaling as well as inflammatory pathways.Tumor microenvironment analysis revealed that NSCLC with CYP2D6 loss manifested increased levels of immunomodulatory gene expressions,PD-L1 expression,relatively high mutational burden and lymphocyte infiltration.DNA methylation alterations were also found to be correlated with m RNA expressions and copy numbers of CYP2D6.Finally,MEK inhibitors were identified by CMap as the prospective therapeutic drugs for CYP2D6 deletion.ConclusionsThese analyses identified novel resistance mechanisms to systemic NSCLC treatments and had significant implications for the development of new treatment strategies.