Dataset Information

Osimertinib for Front-Line Treatment of Locally Advanced or Metastatic EGFR-Mutant NSCLC Patients: Efficacy, Acquired Resistance and Perspectives for Subsequent Treatments.

ABSTRACT: Non-small cell lung cancer (NSCLC) is one of the most efficient models for precision medicine in oncology. The most appropriate therapeutic for the patient is chosen according to the molecular characteristics of the tumor, schematically distributed between immunogenicity and oncogenic addiction. For this last concept, advanced NSCLC with epidermal growth factor receptor (EGFR) mutation is one of the most illustrative models. EGFR-tyrosine kinase inhibitors (TKIs) are the therapeutic backbone for this type of tumor. The recent development of a third-generation TKI, osimertinib, has been a new step forward in the treatment of NSCLC patients. In this article, we first review the clinical development of osimertinib and highlight its efficacy results. We then present the most frequent tumor escape mechanisms when osimertinib is prescribed in first line: off-target (MET amplification, HER2 amplification, BRAF mutation, gene fusions, histologic transformation) and on-target mechanisms (EGFR mutation). Finally, we discuss subsequent biomarker-driven treatment strategies.

SUBMITTER: Denis MG

PROVIDER: S-EPMC7733376 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Osimertinib for Front-Line Treatment of Locally Advanced or Metastatic <i>EGFR</i>-Mutant NSCLC Patients: Efficacy, Acquired Resistance and Perspectives for Subsequent Treatments.

Denis Marc G MG Bennouna Jaafar J

Cancer management and research 20201208

Non-small cell lung cancer (NSCLC) is one of the most efficient models for precision medicine in oncology. The most appropriate therapeutic for the patient is chosen according to the molecular characteristics of the tumor, schematically distributed between immunogenicity and oncogenic addiction. For this last concept, advanced NSCLC with epidermal growth factor receptor (<i>EGFR</i>) mutation is one of the most illustrative models. EGFR-tyrosine kinase inhibitors (TKIs) are the therapeutic backb ...[more]

PMID: 33324104

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

Dataset Information

Osimertinib for Front-Line Treatment of Locally Advanced or Metastatic EGFR-Mutant NSCLC Patients: Efficacy, Acquired Resistance and Perspectives for Subsequent Treatments.

Publications

Osimertinib for Front-Line Treatment of Locally Advanced or Metastatic <i>EGFR</i>-Mutant NSCLC Patients: Efficacy, Acquired Resistance and Perspectives for Subsequent Treatments.

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