TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer

Research output: Contribution to journalArticle

Zhan Yao, Silvia Fenoglio, Ding Cheng Gao, Matthew Camiolo, Brendon Stiles, Trine Lindsted, Michaela Schlederer, Chris Johns, Nasser Altorki, Vivek Mittal, Lukas Kenner, Raffaella Sordella

The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N′-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50%of acquired resistance cases together, in the remaining 50%, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to-mesenchymal transition (EMT). We showed that activation of TGF-β-mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-β-dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-β are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that bothtumor cell-autonomousmechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.

Original languageEnglish
Pages (from-to)15535-15540
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number35
DOIs
StatePublished - Aug 31 2010

PMID: 20713723

PMCID: PMC2932568

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TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. / Yao, Zhan; Fenoglio, Silvia; Gao, Ding Cheng; Camiolo, Matthew; Stiles, Brendon; Lindsted, Trine; Schlederer, Michaela; Johns, Chris; Altorki, Nasser; Mittal, Vivek; Kenner, Lukas; Sordella, Raffaella.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 35, 31.08.2010, p. 15535-15540.

Research output: Contribution to journalArticle

Harvard

Yao, Z, Fenoglio, S, Gao, DC, Camiolo, M, Stiles, B, Lindsted, T, Schlederer, M, Johns, C, Altorki, N, Mittal, V, Kenner, L & Sordella, R 2010, 'TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer' Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 35, pp. 15535-15540. https://doi.org/10.1073/pnas.1009472107

APA

Yao, Z., Fenoglio, S., Gao, D. C., Camiolo, M., Stiles, B., Lindsted, T., ... Sordella, R. (2010). TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 107(35), 15535-15540. https://doi.org/10.1073/pnas.1009472107

Vancouver

Yao Z, Fenoglio S, Gao DC, Camiolo M, Stiles B, Lindsted T et al. TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proceedings of the National Academy of Sciences of the United States of America. 2010 Aug 31;107(35):15535-15540. https://doi.org/10.1073/pnas.1009472107

Author

Yao, Zhan ; Fenoglio, Silvia ; Gao, Ding Cheng ; Camiolo, Matthew ; Stiles, Brendon ; Lindsted, Trine ; Schlederer, Michaela ; Johns, Chris ; Altorki, Nasser ; Mittal, Vivek ; Kenner, Lukas ; Sordella, Raffaella. / TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 35. pp. 15535-15540.

BibTeX

@article{1a990e6a3c4349c6846b2ca229013def,
title = "TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer",
abstract = "The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N′-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50{\%}of acquired resistance cases together, in the remaining 50{\%}, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to-mesenchymal transition (EMT). We showed that activation of TGF-β-mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-β-dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-β are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that bothtumor cell-autonomousmechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.",
keywords = "Epidermal growth-factor receptor, Nonsmall cell lung cancer",
author = "Zhan Yao and Silvia Fenoglio and Gao, {Ding Cheng} and Matthew Camiolo and Brendon Stiles and Trine Lindsted and Michaela Schlederer and Chris Johns and Nasser Altorki and Vivek Mittal and Lukas Kenner and Raffaella Sordella",
year = "2010",
month = "8",
day = "31",
doi = "10.1073/pnas.1009472107",
language = "English",
volume = "107",
pages = "15535--15540",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
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RIS

TY - JOUR

T1 - TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer

AU - Yao, Zhan

AU - Fenoglio, Silvia

AU - Gao, Ding Cheng

AU - Camiolo, Matthew

AU - Stiles, Brendon

AU - Lindsted, Trine

AU - Schlederer, Michaela

AU - Johns, Chris

AU - Altorki, Nasser

AU - Mittal, Vivek

AU - Kenner, Lukas

AU - Sordella, Raffaella

PY - 2010/8/31

Y1 - 2010/8/31

N2 - The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N′-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50%of acquired resistance cases together, in the remaining 50%, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to-mesenchymal transition (EMT). We showed that activation of TGF-β-mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-β-dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-β are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that bothtumor cell-autonomousmechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.

AB - The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N′-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50%of acquired resistance cases together, in the remaining 50%, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to-mesenchymal transition (EMT). We showed that activation of TGF-β-mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-β-dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-β are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that bothtumor cell-autonomousmechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.

KW - Epidermal growth-factor receptor

KW - Nonsmall cell lung cancer

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UR - http://www.scopus.com/inward/citedby.url?scp=77957273623&partnerID=8YFLogxK

U2 - 10.1073/pnas.1009472107

DO - 10.1073/pnas.1009472107

M3 - Article

VL - 107

SP - 15535

EP - 15540

JO - Proceedings of the National Academy of Sciences of the United States of America

T2 - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 35

ER -

ID: 3237491