Hsp90 Inhibition Overcomes HGF-Triggering Resistance to EGFR-TKIs in EGFR-Mutant Lung Cancer by Decreasing Client Protein Expression and Angiogenesis

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Hsp90 Inhibition Overcomes HGF-Triggering Resistance to EGFR-TKIs in EGFR-Mutant Lung Cancer by Decreasing Client Protein Expression and Angiogenesis Hitomi Koizumi, Tadaaki Yamada, MD, PhD, Shinji Takeuchi, MD, PhD, Takayuki Nakagawa, MS, Kenji Kita, MS, Takahiro Nakamura, PhD, Kunio Matsumoto, PhD, Kenichi Suda, MD, PhD, Tetsuya Mitsudomi, MD, PhD, Seiji Yano, MD, PhD Journal of Thoracic Oncology Volume 7, Issue 7, Pages 1078-1085 (July 2012) DOI: 10.1097/JTO.0b013e3182519a2c Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 17-DMAG suppresses the in vitro growth of EGFR mutant lung cancer cells in the presence of HGF. Tumor cells were continuously treated with increasing concentrations of EGFR-TKI, erlotinib (PC-9, HCC827, Ma-1, Ma-1/Vec, and Ma-1/HGF), CL-387,785 (H1975), or 17-DMAG, with or without HGF (20 ng/ml), and cell growth was determined after 72 hours by MTT assay. Data shown are representative of five independent experiments. Error bars indicate SD of triplicate cultures. EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor; TKI, tyrosine kinase inhibitor. Journal of Thoracic Oncology 2012 7, 1078-1085DOI: (10.1097/JTO.0b013e3182519a2c) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 17-DMAG suppresses EGF and Met protein expression and phosphorylation even in the presence of HGF. PC-9, Ma-1, Ma-1/Vec, and Ma-1/HGF tumor cells were treated with or without erlotinib (0.3 μmol/l) or 17-DMAG (0.3 μmol/l) for 24 hours, and then stimulated with or without HGF (20 ng/ml) for 10 minutes. The resultant cells were lysed, and the indicated proteins were detected by immunoblotting. EGF, epidermal growth factor; HGF, hepatocyte growth factor. Journal of Thoracic Oncology 2012 7, 1078-1085DOI: (10.1097/JTO.0b013e3182519a2c) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 17-DMAG overcomes HGF-induced erlotinib resistance in vivo. Ma-1/Vec (A) or Ma-1/HGF (B) cells (5 × 106 each) were inoculated subcutaneously into SCID mice on day 0. Mice received oral erlotinib (20 mg/kg/day) or intraperitoneal 17-DMAG (10 mg/kg/day), starting on day 7. Tumor size was measured twice a week and tumor volumes were calculated as described in Materials and Methods. Error bars indicate SEs of six tumors. C, Macroscopic appearances of representative tumors harvested on day 21. *p < 0.01 compared with the control group (Student's t test). 17-DMAG, 17-Dimethylaminoethylamino-17-demethoxygeldanamycin; HGF, hepatocyte growth factor; SCID, severe combined immunodeficiency. Journal of Thoracic Oncology 2012 7, 1078-1085DOI: (10.1097/JTO.0b013e3182519a2c) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 17-DMAG inhibits EGFR and Met expression in vivo. Ma-1/Vec or Ma-1/HGF cells (5 × 106 each) were inoculated subcutaneously into SCID mice on day 0. Mice received oral erlotinib (20 mg/kg/day) or intraperitoneal 17-DMAG (10 mg/kg/day), starting on day 7. Two hours after treatment on day 11, the mice were sacrificed, and their tumors were harvested and examined histologically. Sections were stained with DAPI (nuclear stain), TUNEL (FITC), EGFR (IHC), and Met (IHC), respectively. Bars indicate 50 μm. 17-DMAG, 17-demethoxygeldanamycin; EGF, epidermal growth factor; HGF, hepatocyte growth factor; SCID, severe combined immunodeficiency; DAPI, 4’,6-diamidino-2-phenylindole; TUNEL, terminal deoxynucleotidyl transferase; FITC, fluorescein isothiocyanate; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry. Journal of Thoracic Oncology 2012 7, 1078-1085DOI: (10.1097/JTO.0b013e3182519a2c) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Quantification of apoptotic and proliferative cells, and of angiogenesis in vivo. A, Apoptotic cells, as determined by the TUNEL assay as described in Materials and Methods. B, Tumor-cell proliferation, as determined by the Ki-67-positive proliferation index (percentage of Ki-67-positive cells). C, Microvessel density, as determined by staining with antimouse-CD31 (clone MEC13.3, BD Bioscience) antibody as described in Materials and Methods. Columns, mean of five areas; bars, SD. *p < 0.05 compared with the control group (Student's t test). TUNEL, terminal deoxynucleotidyl transferase. Journal of Thoracic Oncology 2012 7, 1078-1085DOI: (10.1097/JTO.0b013e3182519a2c) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions