Abstract 1849: Cellullar modifications of glucose uptake through the modulation of AMPK & EGFR signaling axes in lung cancer cell lines

Abstract

Abstract Background. The exacerbated consumption of glucose in tumor cells is a widely reported event, this metabolic modification is associated with the activation of anabolic pathways that contribute to uncontrolled proliferation. Lung cancer tumor cells often present glycolytic metabolism phenotypes with large lactate secretions, due to the fact that they usually develop in hypoxic microenvironments and with low nutrient concentrations. The inhibition of signaling pathways triggered by growth factors receptors, as well as, the activation of AMP-activated protein kinase (AMPK) pathway has the ability to restore a catabolic phenotype in tumor cells thus controlling proliferation and evasion of the immune system. It has been observed that treatment with EGFR tyrosine kinase inhibitors (TKIs) reduces the glycolytic phenotype in certain lung cancer cell lines, on the other hand Metformin has shown a reestablishment of oxidative characteristics in several cell lines of solid tumors. Hypothesis. The Afatinib-Metformin treatment has the ability to modulate the AMPK and EGFR signaling pathways with a decreasing in the glycolytic phenotype in cell lines with different mutational EGFR status. Objective. To determine the effect of combination Afatinib-Metformin on the activation of the EGFR and AMPK pathways and their relationship with glucose consumption in cell lines with different EGFR mutational status. Methods. Three different doses of Afatinib and one dose of Metformin were used in lung adenocarcinoma cell lines A549, H1975 and HCC827 (ATCC). Activation of AMPK and EGFR signaling pathways was assessed by Western Blot and Flow Cytometry. Results. All cell lines showed decreased expression of EGFR as well as its active form. Interestingly LKB1 inhibition was shown with all treatments in H1975 and HCC827 cell lines that express it basally. The evaluation of downstream protein activation of the EGFR pathway showed inhibition of the S6K effector when treatment with Afatinib was administered. As regards the evaluation of glucose uptake all cell lines showed a reduction of up to 50% compared to the control when the combined treatment was administered. Conclusions. The combination treatment Afatinib-Metformin shows regulation of EGFR signaling pathway and inhibition of LKB1 that is one of the activators of AMPK. A down regulation of the incorporation of glucose was shown and this could be associated with a reestablishment of the oxidative character of the metabolic phenotype. Note: This abstract was not presented at the meeting. Citation Format: Pedro Barrios-Bernal, Mario Orozco-Morales, Giovanny Soca-Chafre, Oscar Arrieta, Norma Hernández-Pedro. Cellullar modifications of glucose uptake through the modulation of AMPK & EGFR signaling axes in lung cancer cell lines [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 1849.