Abstract B26: Role of AKT3 in EGFR-TKI resistance of non-small cell lung cancer

Abstract 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 within 9–14 months. Exploring the mechanisms of drug resistance is critical to improve treatment efficacy. 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. HCC827/IR (without T790M) and H1975/AR (without C797S) showed “off-target resistance”. Upregulation of AXL and FGFR1 in HCC827/IR but not H1975/AR cells was found. AKT activation (p-AKT) in parental cells was more sensitive to EGFR-TKI than that in resistant cells. RNA-seq revealed the upregulation of AKT3 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 insensitive to gefitinib and AZD9291 inhibition in resistant cells. Protein but not mRNA of AKT3 was upregulated in gefitinib-treated HCC827/IR and AZD9291-treated H1975/AR cells. AKT3 might serve as a predictive biomarker for EGFR-TKIs therapy. Its upregulation might be one of the mechanisms for EGFR-TKIs acquired resistance. Citation Format: Shih-Hsiang Huang, Jin-Yuan Shih, Ching-Chow Chen. Role of AKT3 in EGFR-TKI resistance of non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B26.