Integrated Omics Analysis of Non-Small-Cell Lung Cancer Cells Harboring the EGFR C797S Mutation Reveals the Potential of AXL as a Novel Therapeutic Target in TKI-Resistant Lung Cancer.

Tong-Hong Wang,Kuo-Yen Huang,Chih-Ching Wu,Shuenn-Chen Yang,Ci-Ling Chen,Chi-Yuan Chen,Yann-Lii Leu

doi:10.3390/cancers13010111

Abstract

Simple SummaryIn this study, we employed CRISPR/Cas9 editing technology to introduce the EGFR C797S mutation into an NSCLC cell line harboring EGFR L858R/T790M to establish a cellular model for the investigation of the resistance mechanism associated with the acquired C797S mutation and to explore strategies to battle this type of TKI resistance. Transcriptome and proteome analyses revealed that the differentially expressed genes/proteins in the cells harboring the EGFR C797S mutation are associated with elevated expression of AXL. Furthermore, we presented evidence that inhibition of AXL is effective in slowing the growth of NSCLC cells harboring EGFR C797S. Our findings suggest that AXL inhibition could be a second-line or a potential adjuvant treatment for NSCLC harboring the EGFR C797S mutation.Oncogenic mutations of epidermal growth factor receptor (EGFR) are responsive to targeted tyrosine kinase inhibitor (TKI) treatment in non-small-cell lung cancer (NSCLC). However, NSCLC patients harboring activating EGFR mutations inevitably develop resistance to TKIs. The acquired EGFR C797S mutation is a known mechanism that confers resistance to third-generation EGFR TKIs such as AZD9291. In this work, we employed CRISPR/Cas9 genome-editing technology to knock-in the EGFR C797S mutation into an NSCLC cell line harboring EGFR L858R/T790M. The established cell model was used to investigate the biology and treatment strategy of acquired EGFR C797S mutations. Transcriptome and proteome analyses revealed that the differentially expressed genes/proteins in the cells harboring the EGFR C797S mutation are associated with a mesenchymal-like cell state with elevated expression of AXL receptor tyrosine kinase. Furthermore, we presented evidence that inhibition of AXL is effective in slowing the growth of NSCLC cells harboring EGFR C797S. Our findings suggest that AXL inhibition could be a second-line or a potential adjuvant treatment for NSCLC harboring the EGFR C797S mutation.

Highlights

Activating mutations of epidermal growth factor receptor (EGFR) are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and are detected in approximately 40% of East Asian patients and 15% of Caucasian patients [1]
To establish cellular models for the investigation of EGFR tyrosine kinase inhibitor (TKI) resistance associated with the acquired C797S mutation in EGFR, we used CRISPR/Cas9 genome editing technology to knock-in the EGFR C797S mutation in non-small-cell lung cancer (NSCLC) H1975 cells
Our overall study design was to employ the EGFR C797S knock-in cells to investigate the biological processes associated with the acquired EGFR C797S mutation by proteomics and transcriptome studies, and to explore the therapeutic strategies

Summary

Introduction

Activating mutations of epidermal growth factor receptor (EGFR) are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and are detected in approximately 40% of East Asian patients and 15% of Caucasian patients [1] These tumors have been termed oncogene addicted to reflect their dependence on the EGFR pathway and their susceptibility to survival inhibition by EGFR tyrosine kinase inhibitors (TKIs) [2]. The first generation (gefitinib and erlotinib) and second generation (afatinib) of TKIs were designed to bind to the ATP binding pocket of the EGFR kinase domain [4] These drugs are superior to chemotherapy in prolonging the progression-free survival (PFS) of NSCLC patients carrying common. The EGFR T790M substitution in exon 20, which inhibits the affinity of these TKIs by increasing steric hindrance, is the most common mechanism for acquired

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