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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.

ABSTRACT: 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.

SUBMITTER: Wang TH

PROVIDER: S-EPMC7795510 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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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.

Wang Tong-Hong TH Wu Chih-Ching CC Huang Kuo-Yen KY Leu Yann-Lii YL Yang Shuenn-Chen SC Chen Ci-Ling CL Chen Chi-Yuan CY

Cancers 20201231 1

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 ...[more]

PMID: 33396393

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Project description:Lessons learnedThis single-arm, phase II study shows that concurrent EGFR-tyrosine kinase inhibitor plus thoracic radiotherapy as the first-line treatment for stage IV non-small cell lung cancer harboring EGFR active mutations provides long-term control for the primary lung lesion, and 1-year progression-free survival (PFS) rate and median PFS are numerically higher than those of the erlotinib monotherapy.Serious adverse events are acceptable, although grade >3 radiation pneumonitis occurred in 20% of patients.BackgroundStudies show effective local control by EGFR-tyrosine kinase inhibitor (TKI) combined with radiotherapy at metastatic sites in advanced lung cancer harboring EGFR active mutations. Salvage local radiotherapy is associated with prolonged progression-free survival (PFS) in local disease during EGFR-TKI treatment. However, no prospective study has been reported on concurrent EGFR-TKI and radiotherapy for primary lung lesions. This study investigated the efficacy and safety of first-line EGFR-TKI combined with thoracic radiotherapy in treating stage IV non-small cell lung cancer (NSCLC) harboring EGFR active mutations.MethodsWe conducted a single-arm, phase II clinical trial. Each patient received EGFR-TKI (erlotinib 150 mg or gefitinib 250 mg per day) plus thoracic radiotherapy (54-60 Gy/27-30 F/5.5-6 w) within 2 weeks of beginning EGFR-TKI therapy until either disease progression or intolerable adverse events (AEs) appeared.ResultsFrom January 2015 to March 2018, 401 patients were screened, and 10 patients (5 male and 5 female) were eligible. These patients had a median age of 55 years (40-75) and median follow-up of 19.8 months (5.8-34). The 1-year PFS rate was 57.1%, median PFS was 13 months, and median time to progression of irradiated lesion (iTTP) was 20.5 months. Objective response rate (ORR), was 50% and disease control rate (DCR) was 100%. The most common grade ≥3 AEs were radiation pneumonitis (20%) and rash (10%). One patient died after rejecting treatment for pneumonitis. The others received a full, systematic course of glucocorticoid therapy. Pneumonitis was all well controlled and did not relapse.ConclusionConcurrent EGFR-TKI plus thoracic radiotherapy as the first-line treatment for stage IV NSCLC harboring EGFR active mutations shows a long-term control of primary lung lesion. The 1-year PFS rate and median PFS of this combined therapy are numerically higher than those of the erlotinib monotherapy. The risk of serious adverse events is acceptable.

Dataset Information

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.

Publications

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.

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