Triple Inhibition of EGFR, Met, and VEGF Suppresses Regrowth of HGF-Triggered, Erlotinib-Resistant Lung Cancer Harboring an EGFR Mutation Junya Nakade,

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Triple Inhibition of EGFR, Met, and VEGF Suppresses Regrowth of HGF-Triggered, Erlotinib-Resistant Lung Cancer Harboring an EGFR Mutation Junya Nakade, MS, Shinji Takeuchi, MD, PhD, Takayuki Nakagawa, MS, Daisuke Ishikawa, MD, Takako Sano, PhD, Shigeki Nanjo, MD, Tadaaki Yamada, MD, PhD, Hiromichi Ebi, MD, PhD, Lu Zhao, MS, Kazuo Yasumoto, MD, PhD, Kunio Matsumoto, PhD, Kazuhiko Yonekura, PhD, Seiji Yano, MD, PhD Journal of Thoracic Oncology Volume 9, Issue 6, Pages 775-783 (June 2014) DOI: 10.1097/JTO.0000000000000170 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Combined use of crizotinib or TAS-115 with erlotinib reverses resistance to EGFR-TKI induced by exogenous HGF. A and B, PC-9 cells were incubated with or without erlotinib or crizotinib and TAS-115 in the presence or absence of HGF (20 ng/ml) for 72 hours. Cell viability was determined by MTT assay. Bars show SD. The data shown are representative of five independent experiments with similar results. EGFR, epidermal growth factor receptor; EGFR-TKI, EGFR-tyrosine kinase inhibitor; HGF, hepatocyte growth factor; MTT, Thiazolyl Blue Tetrazolium Bromide. Journal of Thoracic Oncology 2014 9, 775-783DOI: (10.1097/JTO.0000000000000170) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Combined use of crizotinib or TAS-115 with erlotinib reverses resistance to EGFR-TKI induced by endogenous HGF. A, PC-9/Vec and PC-9/HGF cells were incubated with or without erlotinib for 72 hours. Cell viability was determined by MTT assay. Bars show SD. B and D, PC-9/Vec and PC-9/HGF cells were treated with crizotinib or TAS-115 for 72 hours. C–G, PC-9/Vec and PC-9/HGF cells were incubated with or without erlotinib (0.3 μmol/liter) with or without crizotinib (0.3 μmol/liter) and TAS-115 (1.0 μmol/liter) for 72 hours. The data shown are from three independent experiments with similar results. H and I, PC-9/HGF cells were incubated with TAS-115 (1.0 μmol/liter) or crizotinib (0.3 μmol/liter) and/or erlotinib (0.3 μmol/liter) for 1 hour. Thereafter, cell lysates were harvested, and phosphorylation of the indicated proteins was determined by Western blot analysis. EGFR, epidermal growth factor receptor; EGFR-TKI, EGFR-tyrosine kinase inhibitor; HGF, hepatocyte growth factor; MTT, thiazolyl blue tetrazolium bromide. Journal of Thoracic Oncology 2014 9, 775-783DOI: (10.1097/JTO.0000000000000170) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Crizotinib and TAS-115 inhibits VEGF production by cancer cells and endothelial proliferation. A and B, Tumor cells were incubated with or without HGF (50 ng/ml) in the presence of different concentrations of crizotinib or TAS-115 for 48 hours. Thereafter, supernatants were harvested, and the number of tumor cells was counted. VEGF concentration in the supernatants was determined by ELISA. VEGF levels corrected by the tumor cell number are shown. C and D, HMVECs were incubated in RPMI-1640 medium with 10% FBS (control) or RPMI-1640 medium with 10% FBS in the presence or absence of VEGF (50 ng/ml) with different concentrations of TAS-115, crizotinib, or bevacizumab for 72 hours. Thereafter, cell viability was determined by MTT assay. Bars show SD. The data shown are from three independent experiments with similar results. VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor; ELISA, enzyme-linked immunosorbent assay; HMVECs, human dermal microvascular endothelial cells; FBS, fetal bovine serum; MTT, thiazolyl blue tetrazolium bromide. Journal of Thoracic Oncology 2014 9, 775-783DOI: (10.1097/JTO.0000000000000170) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Treatment with erlotinib plus TAS-115 inhibits angiogenesis in PC-9/HGF tumors in vivo. Nude mice bearing PC-9/Vec or PC-9/HGF tumors (approximately 100 mm3 in size) were administered erlotinib and/or crizotinib and/or TAS-115 orally, once daily for 4 days, and/or bevacizumab intraperitoneally only once. A, The mice were killed on day 4, and the tumors were harvested. B, Numbers of tumor vessels (mean ± SE) determined by CD31 immunohistochemical staining are shown for groups containing five mice each. Representative graphs are shown. The data shown are representative of two independent experiments with similar results. HGF, hepatocyte growth factor. Journal of Thoracic Oncology 2014 9, 775-783DOI: (10.1097/JTO.0000000000000170) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Treatment with erlotinib plus TAS-115 inhibits the growth of PC-9/HGF tumors in vivo. A and B, Nude mice bearing PC-9/Vec or PC-9/HGF tumors (approximately 100 mm3 in size) were administered erlotinib and/or crizotinib and/or TAS-115 orally once daily and/or bevacizumab intraperitoneally once a week. Tumor volume was measured using calipers. Mean ± SE tumor volumes on day 39 are shown for groups containing five mice each. The data shown are representative of two independent experiments with similar results. HGF, hepatocyte growth factor. Journal of Thoracic Oncology 2014 9, 775-783DOI: (10.1097/JTO.0000000000000170) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 6 Treatment with erlotinib plus TAS-115 most strongly prevented the regrowth of PC-9/HGF tumors even after cessation of treatment. A, Nude mice bearing PC-9/HGF tumors were treated as described in Figure 5 until day 39. Thereafter, treatment was terminated, and tumor volume was measured until day 49. B, The mice were killed on day 49, and tumors were harvested. Tumor vessels and apoptotic cells were determined by CD31 immunohistochemical and TUNEL staining, respectively. Asterisk indicates P < 0.01. HGF, hepatocyte growth factor; TUNEL, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick end-labeling. Journal of Thoracic Oncology 2014 9, 775-783DOI: (10.1097/JTO.0000000000000170) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions