Spred-3 mutation and Ras/Raf/MAPK activation confer acquired resistance to EGFR tyrosine kinase inhibitor in an EGFR mutated NSCLC cell line

• DOI: 10.21037/tcr.2020.03.05
• Publication Date: 2020-04-30T08:27:00Z
• Authors: Zhiyong He; Fusheng Gong; Jinrong Liao; Qiang Wang; Ying Su; Chao Chen; Jinghui Lin; Ren-Jang Lin
• Keywords: 03 medical and health sciences; 0302 clinical medicine; Original Article; 3. Good health

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard treatment for advanced non-small cell lung cancer (NSCLC). However, the emergence of EGFR-TKIs resistance poses a big challenge to treatment. Although several resistant mutations have been identified, our understanding mechanisms underlying acquired remains incomplete. This study aimed identify novel and that could contribute in EGFR mutated NSCLC cells.Erlotinib cells (HCC827/ER cells) were generated from line HCC827, whole-exome sequencing was performed gene HCC827/ER cells. The Spred-3 expression determined using quantitative real-time PCR (qPCR) Western blotting assays, p-p44/42, p44/42, p-Akt Akt blotting. half maximal inhibitory concentration (IC50 value) measured MTS assay, migration detected with Transwell assay.Whole-exome identified deletion mutation c.120delG at exon 1 gene, resulting p.E40fs change amino acid, much reduced as compared HCC827 both mRNA protein levels. Knocking out CRISPR/Cas9 increased erlotinib migration, while overexpressing cDNA construct migration. We also showed Ras/Raf/MAPK pathway activated cells, inhibiting ERK1/2 HCC827/Spred-3-sgRNA resulted migration.The results this indicate loss-of-function activation confers harboring an mutation.