Abstract A49: Acquired resistance of non-small cell lung cancer to EGFR-TKI: Role of AKT3

Abstract

Abstract The discovery of EGFR-TKIs has had a dramatic impact on the treatment of NSCLC with EGFR activation mutation. Although they improve the overall survival, the main obstacle is the emergence of acquired resistance. Two resistant cells, HCC827/IR (IRESSA resistance) and H1975/AR (AZD9291 resistance), generated and showing “off-target resistance,” were employed to investigate the molecular and cellular characteristics of the acquired resistance to EGFR-TKIs. AKT activation (p-AKT) in both parental cells was more sensitive to EGFR-TKIs than that in resistant cells. We found that mRNA and protein of AKT3, but not AKT1 and AKT2, were upregulated in both HCC827/IR and H1975/AR cells. Immunoprecipitation of AKT3 demonstrated its contribution to AKT activation. Knockdown of AKT3 in both resistant cells decreased basal AKT activation (p-AKT). However, the insensitive inhibition of gefitinib on AKT activation (p-AKT) in HCC827/IR cells and AZD9291in H1975/AR cells remained even if AKT3 was knocked down. AKT3 protein, but not AKT1 and AKT2, was found to be overexpressed in resistant cells treated with gefitinib or AZD9291 as well as AKT3 KD, indicating the crucial role of AKT3 in acquired resistance to EGFR-TKIs. Combination of AKT inhibitors with AZD9291 showed synergistic inhibition on cell viability of H1975/AR cells. Therefore, AKT3 upregulation might be one of the mechanisms for acquired resistance to EGFR-TKIs, and it might serve as a predictive biomarker for EGFR-TKIs therapy. Citation Format: Shih-Hsiang Huang, Jin-Yuan Shih, Ching-Chow Chen. Acquired resistance of non-small cell lung cancer to EGFR-TKI: Role of AKT3 [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A49.