Program

PO4-6-13

Role of AKT3 in EGFR-TKI resistance of non-small cell lung cancer

[Speaker] Shih-Hsiang Huang:1
[Co-author] Ching-Chow Chen:1, Jin-Yuan Shih:2
1:Pharmacology, National Taiwan University, College of Medicine, Taiwan, 2:Internal Medicine, National Taiwan University Hospital, Taiwan

Background:
Lung cancer is the leading cause of cancer deaths worldwide. EGFR-TKI is the first-line treatment for non-small cell lung cancer (NSCLC) harbouring EGFR mutation. However, most patients develop acquired resistance within 9 to 14 months. Therefore, it is critical to explore the mechanisms of drug resistance to improve treatment efficacy. Two resistant cells, HCC827-IR (Gefitinib or IRESSA-resistance) and H1975-AR (AZD9291-resistance), had been generated. We investigated the molecular and cellular characteristics of the EGFR-TKI acquired resistant cells, which exhibited epithelial-mesenchymal transition (EMT) phenotypes.

Methods:
MTT assay, clonogenic assay were conducted for assessing drug sensitivity. Trans-well assay was used to assess cell migration. RT-PCR, western blot were employed to analyze the mRNA and protein expression.

Results:
AKT3 but not AKT1 and AKT2 was found to be upregulated in both resistant cells. Kaplan Meier Plotter database predicted poor survival of higher AKT3 expression in lung adenocarcinoma patients. The protein but not mRNA of AKT3 was upregulated in Gefitinib or AZD9291-treated HCC827/IR cells. Silence of AKT3 by shRNA in HCC827/IR cells inhibited cell migration and decreased the protein expression of a mesenchymal marker, vimentin. Also, the mRNA level of stemness-related genes was decreased.

Conclusions:
AKT3 might be a biomarker for efficacy of Gefitinib and AZD9291. Its role in EGFR-TKI resistance will be discussed.

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