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EGFR tyrosine kinase inhibitors (TKIs) have greatly improved the prognosis of lung adenocarcinoma. However, approximately 5% to 10% of patients with lung adenocarcinoma with EGFR sensitive mutations have primary resistance to EGFR TKI treatment. The underlying mechanism is unknown.This study used next-generation sequencing to explore the mechanisms of primary resistance by analyzing 11 patients with primary resistance and 11 patients sensitive to EGFR TKIs. Next-generation targeted sequencing was performed on the Illumina X platform for 483 cancer-related genes. EGFR mutation was initially detected using the amplification refractory mutation system.Potential primary resistance mechanisms were revealed by mutations unique to the EGFR TKI resistance group. Among the 11 resistant patients, 45% (five of 11) harbored a known resistance mechanism, such as MNNG HOS Transforming gene (MET) amplification de novo T790M mutation or overlapping T790M and phosphatase and tensin homolog gene (PTEN) loss and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplification. In six of 11 resistant cases (54%), potential novel mutations that might lead to drug resistance were identified (including transforming growth factor beta receptor 1 gene [TGFBR1] mutation and/or EGFR structural rearrangement mechanistic target of rapamycin kinase gene [MTOR] mutation, transmembrane protease, serine 2 gene [TMPRSS2] fusion gene, and v-myc avian myelocytomatosis viral oncogene homolog gene [MYC] amplification). By analyzing somatic mutation patterns, the frequency of C:G→T:A transitions in the patients with primary resistance was significantly higher than that in sensitive group and occurred more frequently in the non-CpG region (Cp(A/C/T)→T).The mechanisms of primary resistance to EGFR TKIs may be highly heterogeneous. Mutations in EGFR and its downstream pathway, as well as mutations that affect tumor cell function, are related to primary resistance. Somatic single-nucleotide mutation patterns might be associated with primary resistance to EGFR TKIs.