Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Lung cancer is the leading cause of cancer deaths worldwide, and EGFR-TKI is the first-line treatment for non-small cell lung cancer (NSCLC) harboring EGFR activation mutation. However, most patients develop acquired resistance around 12 months. Two resistant cells, HCC827/IR (IRESSA resistance) and H1975/AR (AZD9291 resistance) exhibiting EMT phenotypes were generated to investigate the molecular and cellular characteristics of the EGFR-TKI acquired resistance.</jats:p>
<jats:p>The expression and activation of EGFR were reduced in both resistant cells. Upregulation of AXL and FGFR1 were found in HCC827/IR but not H1975/AR cells. HCC827/IR (without T790M) and H1975/AR (without C797S) showed “off target resistance”. Activation of AKT (p-AKT) in both parental cells was more sensitive to EGFR-TKI than that in resistant cells. RNA-seq revealed that AKT3 was upregulated in both resistant cells. High expression of AKT3 was predicted to correlate with the poor survival of lung adenocarcinoma patients. Knockdown of AKT3 in HCC827/IR cells inhibited cell migration and increased the protein expression of E-cadherin, as well as inhibited S phase population to reduce cell proliferation. Knockdown of AKT3 in H1975/AR cells enhanced AZD9291-induced inhibition on AKT activation (p-AKT). Immunoprecipitation of AKT3 in both resistant cells demonstrated its involvement in AKT activation, and AKT3 activation (p-AKT3) was not sensitive to inhibition by gefitinib and AZD9291 in resistant cells. We also found that protein but not mRNA of AKT3 was upregulated in gefitinib-treated HCC827/IR and AZD9291-treated H1975/AR cells. Therefore, AKT3 might serve as a predictive biomarker for EGFR-TKIs therapy, and its upregulation might be one of the mechanisms for EGFR-TKIs acquired resistance. In addition, combination of AZD9291 with AKT inhibitors elicited synergistic inhibition on cell viability of H1975/AR cells.</jats:p>
<jats:p>This work was supported by the National Health Research Institutes (NHRI)- NHRI-EX107-10707BI.</jats:p>
<jats:p>Citation Format: Shih-Hsiang Huang, Jin-Yuan Shih, Ching-Chow Chen. Investigation of AKT3 in the resistance of non-small cell lung cancer to EGFR-TKI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3025.</jats:p>