Enhanced Sensitivity of Nonsmall Cell Lung Cancer with Acquired Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors to Phenformin: The Roles of a Metabolic Shift to Oxidative Phosphorylation and Redox Balance

Figure 1

Acquisition of EGFR-TKI resistance by long-term treatment of gefitinib or erlotinib in NSCLCs. (a and b) Effects of EGFR TKIs on cell proliferation of EGFR TKI-resistant lung cancer cells. HCC827, HCC827 GR, H1993, H1993 ER, H292, H292 ER, and H1975 cells were incubated with various concentrations of gefitinib or erlotinib (a) and osimertinib (b), and cell proliferation was monitored for 72 h by IncuCyte ZOOM analyses. Data represent (, , , vs. parental cell line; ^### vs. H1975). (c) Genomic DNA sequencing of EGFR exon 18 to 21. (d) EGFR and its downstream signaling activities in HCC827, HCC827 GR, H1993, H1993 ER, H292, and H292 ER cells. All cells were pretreated with vehicle or 100 nM gefitinib, erlotinib, or osimertinib for 1 h and then exposed to 100 ng/mL EGF for 5 min. Total cell lysates were subjected to immunoblottings for phospho-EGFR (Tyr1068), phosphor-AKT (Ser473), or phosphor-p44/p42 MAPK (Thr202/Tyr204).

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