Yunguang Sun, PhD, Luigi Moretti, MD, Nicholas J

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Inhibition of JAK2 Signaling by TG101209 Enhances Radiotherapy in Lung Cancer Models Yunguang Sun, PhD, Luigi Moretti, MD, Nicholas J. Giacalone, BS, Stephen Schleicher, BS, Christina K. Speirs, PhD, David P. Carbone, MD, PhD, Bo Lu, MD, PhD Journal of Thoracic Oncology Volume 6, Issue 4, Pages 699-706 (April 2011) DOI: 10.1097/JTO.0b013e31820d9d11 Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 TG101209 inhibits survivin and reduces phosphorylation of STAT3 in HCC2429 and H460 lung cancer cells. HCC2429 and H460 cells were treated with 1 or 3 μM TG101209 for 24 or 48 hours. Shown are results of Western blots using labeled antibodies to phospho- and total STAT3, survivin, pro-caspase-3, and cleaved caspase-3. Actin was probed to demonstrate equal loading. Journal of Thoracic Oncology 2011 6, 699-706DOI: (10.1097/JTO.0b013e31820d9d11) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Radiosensitization of HCC2429 and H460 lung cancer cells by TG101209. HCC2429 (A) or H460 (B) cells were treated with 1 μM TG101209 or DMSO for 2 hours followed by irradiation with the indicated doses. Forty-eight hours after radiation, drug-containing media was replaced with fresh media. After 8 days, surviving colonies were stained and scored. Shown are survival curves containing the mean ± SD of three separate, repeated experiments. Journal of Thoracic Oncology 2011 6, 699-706DOI: (10.1097/JTO.0b013e31820d9d11) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Effects of radiation and TG101209 on PI3K/Akt and Ras/MAPK/ERK pathways. HCC2429 and H460 cells were treated with 6 Gy radiation (A) or 1 μM TG101209 (B) for 30 minutes, 1, 2, 4, and 24 hours, or DMSO control. Shown are results of Western blots using labeled antibodies to phospho- and total STAT3, phospho- and total Akt, phospho- and total ERK, and survivin. Actin was probed to demonstrate equal loading. Journal of Thoracic Oncology 2011 6, 699-706DOI: (10.1097/JTO.0b013e31820d9d11) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Radiation- and TG101209-induced apoptosis is modulated by KRAS mutation status in lung cancer cells. HCC2429 KRAS wild-type cells were transfected with a plasmid containing the KRAS G12V mutation and then were treated with either DMSO control, 1 or 3 μM TG101209 (A), or 0, 6, and 10 Gy radiation (B) for 24 and 48 hours. Shown are results of Western blots using labeled antibodies to pro-caspase-3, cleaved caspase-3, and human influenza hemagglutinin (HA). (C), Forty-eight hours after transfection, untreated wild-type and KRAS-mutated HCC2429 cells were collected for Western blot and probed with antibodies to phospho- and total STAT3, phospho- and total ERK, phospho- and total Akt, and survivin. Actin was probed to demonstrate equal loading. Journal of Thoracic Oncology 2011 6, 699-706DOI: (10.1097/JTO.0b013e31820d9d11) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Combination of TG101209 and radiation prolongs tumor growth delay in lung cancer xenograft model. HCC2429 lung cancer cells (1 × 106 cells in 100 μl DMEM) were injected subcutaneously into athymic nude mice. After 6 to 8 days, mice were treated with vehicle control, TG101209 (100 mg/kg twice a day for 7 consecutive days), radiotherapy, or combined TG101209 and radiotherapy (mice were irradiated 1 hour after TG101209 treatment with 2 Gy daily for 5 consecutive days). Tumor growth delay as defined by the number of days required to reach a tumor volume of 0.4 cm3 was measured. Tumors were measured regularly and growth delay was calculated for treatment groups relative to control. Journal of Thoracic Oncology 2011 6, 699-706DOI: (10.1097/JTO.0b013e31820d9d11) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 6 TG101209 with radiation reduces Ki-67 proliferative marker and blood vessel density and increases apoptosis in lung tumor xenograft model. Histological sections were obtained from the tumors of the mice in each treatment group from the tumor volume study. A, Staining for Ki-67 was performed to assess cell proliferation and the number of positive cells was scored and graphed by averaging three repeated experiments. B, Slides were stained for von Willebrand factor (vWF) using anti-vWF antibody to determine vessel density and the number of blood vessels per random 400× fields was scored and graphed by averaging three repeated experiments. C, Staining for active caspase-3 was performed to measure apoptosis and the number of positive cells was scored and graphed by averaging three repeated experiments; *p < 0.05. Journal of Thoracic Oncology 2011 6, 699-706DOI: (10.1097/JTO.0b013e31820d9d11) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions