Data from: Exogenous restoration of TUSC2 expression induces responsiveness to erlotinib in wildtype epidermal growth factor receptor (EGFR) lung cancer cells through context specific pathways resulting in enhanced therapeutic efficacy
Dai, Bingbing, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Yan, Shaoyu, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Lara-Guerra, Humberto, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Kawashima, Hiroyuki, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Sakai, Ryo, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Jayachandran, Gitanjali, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Majidi, Mourad, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Mehran, Reza, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Wang, Jing, Department of Bioinfomatics and Computational Biology, UT MD Anderson Cancer Center, Houston, Texas, United States of America
Bekele, Nebiyou, Department of Biostatistics, UT MD Anderson Cancer Center, Houston, Texas, United States of America
Baladandayuthapani, Veerabhadran, Department of Biostatistics, UT MD Anderson Cancer Center, Houston, Texas, United States of America
Yoo, Suk-Young, Department of Bioinfomatics and Computational Biology, UT MD Anderson Cancer Center, Houston, Texas, United States of America
Wang, Ying, Department of Bioinfomatics and Computational Biology, UT MD Anderson Cancer Center, Houston, Texas, United States of America
Ying, Jun, Department of Biostatistics, UT MD Anderson Cancer Center, Houston, Texas, United States of America
Meng, Feng, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Ji, Lin, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Roth, Jack A., Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, United States of America
Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild type EGFR non-small cell lung cancer (NSCLC) cell lines resistant to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2-erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR.
A549-siRNA-FGFR2-ER
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AZD4547-Erlotinib combinaiton in A549 cells repeat
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AZD4547-Erlotinib combination in A549, H1299 H1650
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Copy of heatmap-rawdata-normdata
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Copy of result-heatmap-GeneExp
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Copy of result-heatmap-RPPA
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H1299 h322 h460 rapa-er combination
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Raw data - in vivo effect of TUSC2 + ER
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Raw data - TUSC2 repressed FGFR2 expression in H1299 cells
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Raw data - TUSC2 expression