title: TUSC2(FUS1)-erlotinib Induced Vulnerabilities in Epidermal Growth Factor Receptor(EGFR) Wildtype Non-small Cell Lung Cancer(NSCLC) Targeted by the Repurposed Drug Auranofin.
abstract: Expression of the TUSC2/FUS1 tumor suppressor gene in TUSC2 deficient EGFR wildtype lung cancer cells increased sensitivity to erlotinib. Microarray mRNA expression analysis of TUSC2 inducible lung cancer cells treated with erlotinib uncovered defects in the response to oxidative stress suggesting that increasing reactive oxygen species (ROS) would enhance therapeutic efficacy. Addition of the thioredoxin reductase 1 inhibitor (TXNRD1) auranofin (AF) to NSCLC cells treated with combination of TUSC2 forced expression with erlotinib increased tumor cell apoptosis and inhibited colony formation. TXNRD1 overexpression rescued tumors from AF-TUSC2-erlotinib induced apoptosis. Neutralizing ROS with nordihydroguaiaretic acid (NDGA) abrogated cell death induced by AF-TUSC2-erlotinib, indicating a regulatory role for ROS in the efficacy of the three drug combination. Isobologram-based statistical analysis of this combination demonstrated superior synergism, compared with each individual treatment at lower concentrations. In NSCLC tumor xenografts, tumor growth was markedly inhibited and animal survival was prolonged over controls by AF-TUSC2-erlotinib. Microarray mRNA expression analysis uncovered oxidative stress and DNA damage gene signatures significantly upregulated by AF-TUSC2-erlotinib compared to TUSC2-erlotinib. Pathway analysis showed the highest positive z-score for the NRF2-mediated oxidative stress response. Taken together these findings show that the combination of TUSC2-erlotinib induces additional novel vulnerabilities that can be targeted with AF.
authors.affiliation: Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Cao
authors.initials: C
authors.lastname: Xiaobo
authors.affiliation: Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, TX, USA.
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, TX, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Feng
authors.affiliation: Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ruping
authors.initials: R
authors.lastname: Shao
authors.affiliation: Department of Bioinfomatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Bioinfomatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Biostatistics, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Veerabhadran
authors.initials: V
authors.lastname: Baladandayuthapani
authors.affiliation: Department of Biostatistics, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Juhee
authors.initials: J
authors.lastname: Song
authors.affiliation: Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
authors.affiliation: Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, TX, USA.
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, TX, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Mehran
authors.affiliation: Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
mesh_terms: D001310:Auranofin / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C499993:TUSC2 protein, human; D025521:Tumor Suppressor Proteins; D001310:Auranofin; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors