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

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

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 rec...

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Main Authors: Dai, Bingbing, Yan, Shaoyu, Lara-Guerra, Humberto, Kawashima, Hiroyuki, Sakai, Ryo, Jayachandran, Gitanjali, Majidi, Mourad, Mehran, Reza, Wang, Jing, Bekele, B. Nebiyou, Baladandayuthapani, Veerabhadran, Yoo, Suk-Young, Wang, Ying, Ying, Jun, Meng, Feng, Ji, Lin, Roth, Jack A.
Format: Online
Language:English
Published: Public Library of Science 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460038/
id pubmed-4460038
recordtype oai_dc
spelling pubmed-44600382015-06-16 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 Yan, Shaoyu Lara-Guerra, Humberto Kawashima, Hiroyuki Sakai, Ryo Jayachandran, Gitanjali Majidi, Mourad Mehran, Reza Wang, Jing Bekele, B. Nebiyou Baladandayuthapani, Veerabhadran Yoo, Suk-Young Wang, Ying Ying, Jun Meng, Feng Ji, Lin Roth, Jack A. Research Article 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. Public Library of Science 2015-06-08 /pmc/articles/PMC4460038/ /pubmed/26053020 http://dx.doi.org/10.1371/journal.pone.0123967 Text en © 2015 Dai et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Dai, Bingbing
Yan, Shaoyu
Lara-Guerra, Humberto
Kawashima, Hiroyuki
Sakai, Ryo
Jayachandran, Gitanjali
Majidi, Mourad
Mehran, Reza
Wang, Jing
Bekele, B. Nebiyou
Baladandayuthapani, Veerabhadran
Yoo, Suk-Young
Wang, Ying
Ying, Jun
Meng, Feng
Ji, Lin
Roth, Jack A.
spellingShingle Dai, Bingbing
Yan, Shaoyu
Lara-Guerra, Humberto
Kawashima, Hiroyuki
Sakai, Ryo
Jayachandran, Gitanjali
Majidi, Mourad
Mehran, Reza
Wang, Jing
Bekele, B. Nebiyou
Baladandayuthapani, Veerabhadran
Yoo, Suk-Young
Wang, Ying
Ying, Jun
Meng, Feng
Ji, Lin
Roth, Jack A.
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
author_facet Dai, Bingbing
Yan, Shaoyu
Lara-Guerra, Humberto
Kawashima, Hiroyuki
Sakai, Ryo
Jayachandran, Gitanjali
Majidi, Mourad
Mehran, Reza
Wang, Jing
Bekele, B. Nebiyou
Baladandayuthapani, Veerabhadran
Yoo, Suk-Young
Wang, Ying
Ying, Jun
Meng, Feng
Ji, Lin
Roth, Jack A.
author_sort Dai, Bingbing
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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
description 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.
publisher Public Library of Science
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460038/
_version_ 1613233161112649728

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