title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Dai
authors.affiliation: 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.
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Humberto
authors.initials: H
authors.lastname: Lara-Guerra
authors.affiliation: 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; Nigata University Graduate School of Medical and Dental Sciences, Nigata, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawashima
authors.affiliation: 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; Okayama Citizens' Hospital, Okayama, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Sakai
authors.affiliation: 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.
authors.forename: Gitanjali
authors.initials: G
authors.lastname: Jayachandran
authors.affiliation: 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.
authors.forename: Mourad
authors.initials: M
authors.lastname: Majidi
authors.affiliation: 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.
authors.forename: Reza
authors.initials: R
authors.lastname: Mehran
authors.affiliation: Department of Bioinfomatics and Computational Biology, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, UT MD Anderson Cancer Center, Houston, Texas, United States of America; Gilead Sciences, Foster City, California, United States of America.
authors.forename: B Nebiyou
authors.initials: BN
authors.lastname: Bekele
authors.affiliation: Department of Biostatistics, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Veerabhadran
authors.initials: V
authors.lastname: Baladandayuthapani
authors.affiliation: Department of Bioinfomatics and Computational Biology, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Suk-Young
authors.initials: SY
authors.lastname: Yoo
authors.affiliation: Department of Bioinfomatics and Computational Biology, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, UT MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Ying
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Meng
authors.affiliation: 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Ji
authors.affiliation: 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.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C572463:AZD4547; D001549:Benzamides; D010879:Piperazines; D011720:Pyrazoles; C499993:TUSC2 protein, human; D025521:Tumor Suppressor Proteins; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D051497:Receptor, Fibroblast Growth Factor, Type 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus