Analysis of ERBB Ligand-Induced Resistance Mechanism to Crizotinib by Primary Culture of Lung Adenocarcinoma with EML4-ALK Fusion Gene Madoka Kimura,

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Analysis of ERBB Ligand-Induced Resistance Mechanism to Crizotinib by Primary Culture of Lung Adenocarcinoma with EML4-ALK Fusion Gene Madoka Kimura, MD, Hiroko Endo, PhD, Takako Inoue, MD, Kazumi Nishino, MD, PhD, Junji Uchida, MD, PhD, Toru Kumagai, MD, PhD, Yoji Kukita, PhD, Kikuya Kato, MD, PhD, Fumio Imamura, MD, PhD, Masahiro Inoue, MD, PhD Journal of Thoracic Oncology Volume 10, Issue 3, Pages 527-530 (March 2015) DOI: 10.1097/JTO.0000000000000381 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Clinical course of the patient. Crizotinib was started on her 2nd day in the hospital. The solid line indicates serum CEA value. The arrow with LB53 indicates the time when pleural effusion was obtained to establish CTOSs (LB53 cells). Time points of plural effusion sampling are indicated as PE 1 and PE 2. A month is defined as 28 days. CEA, carcinoembryonic antigen; CTOSs, cancer tissue-originated spheroids; PE, pleural effusion. Journal of Thoracic Oncology 2015 10, 527-530DOI: (10.1097/JTO.0000000000000381) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Chest radiography (upper panels) and CT (lower panels) before and after treatment with crizotinib. Chest radiography and chest CT examination after treatment were performed on the 28th day and on the 22nd day in the hospital, respectively. CT, computed tomography. Journal of Thoracic Oncology 2015 10, 527-530DOI: (10.1097/JTO.0000000000000381) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Activation of ERBB signaling by EGF or NRG-1 decreased crizotinib sensitivity. A, In vitro dose–response curve of crizotinib in LB53. CTOSs were cultured under growth factor-free conditions (closed circle), with 10 ng/ml of EGF (open circle), or with NRG-1 (open triangle); CTOSs were then treated with crizotinib for 7 days. Averages and standard deviation are shown. IC50 is listed above the graph. B, Representative image of CTOSs treated with 1 μM crizotinib in the presence of 10 ng/ml of NRG1, EGF, bFGF, activin A or 100 ng/ml of long-IGF1, IL-6, and IL-6Rα or 50 ng/ml of HGF for 7 days. C, Western blot of the ALK or ERBB signaling pathways in LB53. CTOSs were cultured under growth factor-free conditions and pulsed with 10 ng/ml of EGF or NRG-1 for 15 minutes in the presence or absence of 1 μM crizotinib. ALK, anaplastic lymphoma kinase; bFGF, basic fibroblast growth factor; CTOSs, cancer tissue-originated spheroids; EGF, epidermal growth factor; HGF, hepacyte growth factor; IC50, half maximal inhibitory concentration; NRG-1, neuregulin-1. Journal of Thoracic Oncology 2015 10, 527-530DOI: (10.1097/JTO.0000000000000381) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Erlotinib restored crizotinib sensitivity in the presence of EGF. A, Western blot of ALK and ERBB signaling pathways in LB53. CTOSs were cultured under growth factor-free conditions over night, and then stimulation for 15 minutes was performed with patient's own pleural effusion, or with the medium containing 10 ng/ml of EGF or NRG-1. Pleural effusion drawn at two different time points was examined (Pleural effusion 1 and 2). B, In vitro dose–response curve of crizotinib in LB53 cells. CTOSs were cultured in medium containing 10 ng/ml of EGF with (closed circle) or without (open circle) 1 μM of erlotinib. Average and standard deviation are shown. IC50 is listed above the graph. C, Western blot of ALK or the ERBB signaling pathway in LB53. CTOSs were cultured under growth factor-free conditions and pulsed with 10 ng/ml EGF for 15 minutes in the presence or absence of 1 μM crizotinib and/or 1 μM erlotinib. EGF, epidermal growth factor; NRG-1, neuregulin-1; CTOSs, cancer tissue-originated spheroids; ALK, anaplastic lymphoma kinase. Journal of Thoracic Oncology 2015 10, 527-530DOI: (10.1097/JTO.0000000000000381) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions