Mutational profiling of non-small-cell lung cancer patients resistant to first-generation EGFR tyrosine kinase inhibitors using next generation sequencing

Abstract

Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is secondary EGFR-T790M mutation. Other mechanisms, such as HER2 and MET amplifications, and PIK3CA mutations, were also reported. However, the mechanisms in the remaining patients are still unknown. In this study, we performed mutational profiling in a cohort of 83 NSCLC patients with TKI-sensitizing EGFR mutations at diagnosis and acquired resistance to three different first-generation EGFR TKIs using targeted next generation sequencing (NGS) of 416 cancer-related genes. In total, we identified 322 genetic alterations with a median of 3 mutations per patient. 61% of patients still exhibit TKI-sensitizing EGFR mutations, and 36% of patients acquired EGFR-T790M. Besides other known resistance mechanisms, we identified TET2 mutations in 12% of patients. Interestingly, we also observed SOX2 amplification in EGFR-T790M negative patients, which are restricted to Icotinib treatment resistance, a drug widely used in Chinese NSCLC patients. Our study uncovered mutational profiles of NSCLC patients with first-generation EGFR TKIs resistance with potential therapeutic implications.

Non‐small cell lung cancer harboring a rare EGFR L747P mutation showing intrinsic resistance to both gefitinib and osimertinib (AZD9291): A case report

“…23 SOX2 amplification is reported to correlate with resistance to icotinib in EGFR-T790M negative patients. 10,24 However, the impact of the TP53 mutation on resistance to TKIs in this case is unclear.…”

“…Primary resistance refers to the immediate inefficacy of EGFR ‐TKIs, while acquired resistance is progression of the disease after a duration of clinical benefit. Acquired resistance to TKIs in patients with advanced NSCLC harboring sensitive EGFR mutations has been well documented; however, knowledge of primary TKI resistance is limited.…”

CUX1-ALK, a Novel ALK Rearrangement That Responds to Crizotinib in Non–Small Cell Lung Cancer

“…Tumor genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) sections followed by targeted NGS sequencing as previously described. 9 Sequencing data were mapped onto human hg19, and genomic fusions were identified by using the Fusion and Chromosomal Translocation Enumeration and Recovery Algorithm with default parameters. Total RNA extracted from FFPE sections was subjected to RNA sequencing on the Illumina HiSeq 4000 platform (Illumina, San Diego, CA).…”

“…In July 2015, FFPE sections of the primary tumor were subjected to comprehensive NGS with a pan-cancer gene panel. 9 The mutation profile showed a rearrangement between chromosome 2 and chromosome 7 with a mutant allele frequency of 11% ( Fig. 2A).…”

Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer

“…This irreversible binding of the receptor often leads to more severe on-target side effects like skin rash and diarrhea. A meta-analysis on 3000 patients showed that afatinib has a limited effect on the L858R mutation, whereas it has higher efficacy against the exon 19 deletion [35,36] . The exon 20 insertion also leads to innate resistance against afatinib.…”