Abstract
BackgroundMolecular targeted therapy for non-small cell lung carcinoma (NSCLC) is restricted due to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This study evaluated the effects of dual targeting of MEK and PI3K in human EGFR-TKI resistant NSCLC cell lines.MethodsEGFR-TKI resistant NSCLC cell lines H1975, H460, and A549, with different mutation and amplification status in EGFR, K-RAS, PIK3CA, and MET genes, were treated with a MEK162 (MEK inhibitor) and BKM120 (PI3K inhibitor) combination or a BIBW2992 (EGFR inhibitor) and ARQ197 (MET inhibitor) combination and assayed for cell proliferation, apoptosis, and cell cycle distribution.ResultsDual targeting of MEK and PI3K efficiently inhibited the cell proliferation, induced apoptosis and the G0/G1 cell cycle, and decreased the phosphorylation of ERK1/2, AKT, S6, and 4E-BP1. H460 cells with K-RAS and PIK3CA mutation were most sensitive to MEK162 and BKM120 combinations. H1975 cells with EGFR and PIK3CA mutation and MET amplification were sensitive to BIBW2992 and ARQ197 combinations.ConclusionDual targeting regulated the proliferation of EGFR-TKI-resistant NSCLC cells, especially mutants in K-RAS and PIK3CA that are promising for EGFR-TKI-resistant NSCLC therapeutics.
Highlights
Molecular targeted therapy for non-small cell lung carcinoma (NSCLC) is restricted due to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)
In the current study, we evaluated the efficacy of the MEK162/ BKM120 combination to inhibit MAP kinase-extracellular-signal-regulated kinase (ERK) kinase (MEK) and PI3K pathways and analyzed the effect on cell proliferation, apoptosis, and cell cycle distribution in a panel of three different human NSCLC cell lines selected according to their mutation and amplification status for EGFR, MET, KRAS, and PIK3CA genes
MEK162/BKM120 combination inhibits the viability of human EGFR‐TKI resistant NSCLC cell lines with different genetic backgrounds H1975, H460, and A549 cells were treated with MEK162 (0–3 μM) or BKM120 (0–15 μM) or in combination for 48 h
Summary
Molecular targeted therapy for non-small cell lung carcinoma (NSCLC) is restricted due to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This study evaluated the effects of dual targeting of MEK and PI3K in human EGFR-TKI resistant NSCLC cell lines. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been indicated to play a significant role in the pathogenesis and progression of tumorigenesis [1]. Targeted therapies involving the use of EGFR tyrosine kinase inhibitor (TKI) as a first-line of therapeutic agents in patients with non-small cell lung cancer (NSCLC) with EGFR activating mutations Resistance to the EGFR-TKI markedly limits its clinical use [4, 5]. PIK3CA mutations can contribute toward EGFR-TKIs resistance
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