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Current Approaches in NSCLC Targeting K-RAS and EGFR.

ABSTRACT: The research and treatment of non-small cell lung cancer (NSCLC) have achieved some important advances in recent years. Nonetheless, the overall survival rates for NSCLC remain low, indicating the importance to effectively develop new therapies and improve current approaches. The understanding of the function of different biomarkers involved in NSCLC progression, survival and response to therapy are important for the development of early detection tools and treatment options. Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (K-RAS) are two of the main significant biomarkers for the management of NSCLC. Mutations in these genes were associated with development and response to therapies. For example, the use of small molecule tyrosine kinase (TK) inhibitors and immunotherapy has led to benefits in some, but not all patients with altered EGFR. In contrast, there is still no effective approved drug to act upon patients harbouring K-RAS mutations. In addition, K-RAS mutations have been associated with lack of activity of TK inhibitors. However, promising approaches aimed to inhibit mutant K-RAS are currently under study. Therefore, this review will discuss these approaches and also EGFR therapies, and hopefully, it will draw attention to the need of continued research in the field in order to improve the outcomes in NSCLC patients.

SUBMITTER: Aran V

PROVIDER: S-EPMC6888213 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Current Approaches in NSCLC Targeting K-RAS and EGFR.

Aran Veronica V Omerovic Jasminka J

International journal of molecular sciences 20191114 22

The research and treatment of non-small cell lung cancer (NSCLC) have achieved some important advances in recent years. Nonetheless, the overall survival rates for NSCLC remain low, indicating the importance to effectively develop new therapies and improve current approaches. The understanding of the function of different biomarkers involved in NSCLC progression, survival and response to therapy are important for the development of early detection tools and treatment options. Epidermal growth fa ...[more]

PMID: 31739412

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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.

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Current Approaches in NSCLC Targeting K-RAS and EGFR.

Publications

Current Approaches in NSCLC Targeting K-RAS and EGFR.

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