V843I, a Lung Cancer Predisposing EGFR Mutation, Is Responsible for Resistance to EGFR Tyrosine Kinase Inhibitors Satsuki Matsushima, BSc, Kouki Ohtsuka,

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V843I, a Lung Cancer Predisposing EGFR Mutation, Is Responsible for Resistance to EGFR Tyrosine Kinase Inhibitors Satsuki Matsushima, BSc, Kouki Ohtsuka, MD, PhD, Hiroaki Ohnishi, MD, PhD, Masachika Fujiwara, MD, PhD, Hiroyuki Nakamura, PhD, Takeshi Morii, MD, PhD, Tomonori Kishino, MD, PhD, Hajime Goto, MD, PhD, Takashi Watanabe, MD, PhD Journal of Thoracic Oncology Volume 9, Issue 9, Pages 1377-1384 (September 2014) DOI: 10.1097/JTO.0000000000000241 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Phosphorylation assay of EGFR and its downstream signal proteins by flow cytometry. The black and white columns indicate the mean percentages of cells with (A) EGFR phosphorylated at Y1068 (pEGFR), (B) STAT5 phosphorylated at Y694 (pSTAT5), (C) ERK1/2 phosphorylated at T202/Y204 (pERK1/2), and (D) Akt phosphorylated at Ser473 (pAkt), before and after epithelial growth factor (EGF) stimulation, respectively. Each experiment was performed three times. *p less than 0.05, compared with wtEGFR-3T3 under stimulation of EGF. Bars indicate standard deviations. Journal of Thoracic Oncology 2014 9, 1377-1384DOI: (10.1097/JTO.0000000000000241) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 MTS assay for susceptibility of lung adenocarcinoma cell lines to (A) erlotinib (B) gefitinib, and (C) afatinib and dacomitinib. KCI-PLA1 was resistant to gefitinib, erlotinib, afatinib, or dacomitinib at concentrations of up to 10-100 μM. Each experiment was repeated three times. Bars indicate standard deviations. Journal of Thoracic Oncology 2014 9, 1377-1384DOI: (10.1097/JTO.0000000000000241) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Effect of EGFR V843I-specific siRNA on susceptibility of lung adenocarcinoma cell lines to EGFR-tyrosine kinase inhibitors AG1478. A, Cell viability of KCI-PLA1 (with V843I and L858R) in the presence of 10 or 100 μM of AG1478 was eliminated by addition of 100 nM of V843I-specific siRNA1, whereas this effect was not evident upon addition of nonspecific siRNA. (B–D) Addition of V843I-specific siRNA1 did not affect cell viability of NCI-1975, 11–18, or A549 compared with addition of nonspecific siRNA. Each experiment was repeated three times. Bars indicate standard deviations. (E, F) Apoptosis of KCI-PLA1 cells treated by siRNA alone (E) or siRNA + AG1478 (F). FL1 denotes the fluorescence intensity of annexin-positive cells, and FL2 denotes the fluorescence intensity of propidium iodide-positive cells. A large part of dead cells displayed an apoptotic pattern (right lower quadrant). Note that few cells were dead (annexin-positive) when treated by siRNA alone. Journal of Thoracic Oncology 2014 9, 1377-1384DOI: (10.1097/JTO.0000000000000241) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Predicted tyrosine kinase inhibitors binding site structures of wild-type EGFR (A) and mutated EGFRs harboring L858R (B), T790M (C), L858R + V843I (D), or L858R + T790M (E) substitutions. The mutated protein models were built using the homology modeling program of DS modeling version 2.0 (Accelrys, San Diego, CA) based on the crystallographic structure of the EGFR protein kinase domain, solved in complex with erlotinib (PDB code: 1M17). Journal of Thoracic Oncology 2014 9, 1377-1384DOI: (10.1097/JTO.0000000000000241) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions