Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1

Valentina Pirazzoli, Caroline Nebhan, Xiaoling Song, Anna Wurtz, Zenta Walther, Guoping Cai, Zhongming Zhao, Peilin Jia, Elisa de Stanchina, Erik M. Shapiro, Molly Gale, Ruonan Yin, Leora Horn, David P. Carbone, Philip J. Stephens, Vincent Miller, Scott Gettinger, William Pao, Katerina Politi

    Research output: Research - peer-reviewArticle

    • 33 Citations

    Abstract

    Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.

    LanguageEnglish (US)
    Pages999-1008
    Number of pages10
    JournalCell Reports
    Volume7
    Issue number4
    DOIs
    StatePublished - May 22 2014

    Profile

    Protein-Tyrosine Kinases
    Cetuximab
    mechanistic target of rapamycin complex 1
    BIBW 2992
    Adenocarcinoma of lung
    Chemical activation
    Drug Resistance
    Pharmaceutical Preparations
    Drug Combinations
    Sirolimus
    Biopsy
    Antibodies
    Genes
    Therapeutics

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

    Cite this

    Pirazzoli, V., Nebhan, C., Song, X., Wurtz, A., Walther, Z., Cai, G., ... Politi, K. (2014). Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1. Cell Reports, 7(4), 999-1008. DOI: 10.1016/j.celrep.2014.04.014

    Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1. / Pirazzoli, Valentina; Nebhan, Caroline; Song, Xiaoling; Wurtz, Anna; Walther, Zenta; Cai, Guoping; Zhao, Zhongming; Jia, Peilin; de Stanchina, Elisa; Shapiro, Erik M.; Gale, Molly; Yin, Ruonan; Horn, Leora; Carbone, David P.; Stephens, Philip J.; Miller, Vincent; Gettinger, Scott; Pao, William; Politi, Katerina.

    In: Cell Reports, Vol. 7, No. 4, 22.05.2014, p. 999-1008.

    Research output: Research - peer-reviewArticle

    Pirazzoli, V, Nebhan, C, Song, X, Wurtz, A, Walther, Z, Cai, G, Zhao, Z, Jia, P, de Stanchina, E, Shapiro, EM, Gale, M, Yin, R, Horn, L, Carbone, DP, Stephens, PJ, Miller, V, Gettinger, S, Pao, W & Politi, K 2014, 'Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1' Cell Reports, vol 7, no. 4, pp. 999-1008. DOI: 10.1016/j.celrep.2014.04.014
    Pirazzoli V, Nebhan C, Song X, Wurtz A, Walther Z, Cai G et al. Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1. Cell Reports. 2014 May 22;7(4):999-1008. Available from, DOI: 10.1016/j.celrep.2014.04.014
    Pirazzoli, Valentina ; Nebhan, Caroline ; Song, Xiaoling ; Wurtz, Anna ; Walther, Zenta ; Cai, Guoping ; Zhao, Zhongming ; Jia, Peilin ; de Stanchina, Elisa ; Shapiro, Erik M. ; Gale, Molly ; Yin, Ruonan ; Horn, Leora ; Carbone, David P. ; Stephens, Philip J. ; Miller, Vincent ; Gettinger, Scott ; Pao, William ; Politi, Katerina. / Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1. In: Cell Reports. 2014 ; Vol. 7, No. 4. pp. 999-1008
    @article{f41e1aabffa640e6bb357144702b15c4,
    title = "Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1",
    abstract = "Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.",
    author = "Valentina Pirazzoli and Caroline Nebhan and Xiaoling Song and Anna Wurtz and Zenta Walther and Guoping Cai and Zhongming Zhao and Peilin Jia and {de Stanchina}, Elisa and Shapiro, {Erik M.} and Molly Gale and Ruonan Yin and Leora Horn and Carbone, {David P.} and Stephens, {Philip J.} and Vincent Miller and Scott Gettinger and William Pao and Katerina Politi",
    year = "2014",
    month = "5",
    doi = "10.1016/j.celrep.2014.04.014",
    volume = "7",
    pages = "999--1008",
    journal = "Cell Reports",
    issn = "2211-1247",
    publisher = "Cell Press",
    number = "4",

    }

    TY - JOUR

    T1 - Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1

    AU - Pirazzoli,Valentina

    AU - Nebhan,Caroline

    AU - Song,Xiaoling

    AU - Wurtz,Anna

    AU - Walther,Zenta

    AU - Cai,Guoping

    AU - Zhao,Zhongming

    AU - Jia,Peilin

    AU - de Stanchina,Elisa

    AU - Shapiro,Erik M.

    AU - Gale,Molly

    AU - Yin,Ruonan

    AU - Horn,Leora

    AU - Carbone,David P.

    AU - Stephens,Philip J.

    AU - Miller,Vincent

    AU - Gettinger,Scott

    AU - Pao,William

    AU - Politi,Katerina

    PY - 2014/5/22

    Y1 - 2014/5/22

    N2 - Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.

    AB - Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.

    UR - http://www.scopus.com/inward/record.url?scp=84901275269&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84901275269&partnerID=8YFLogxK

    U2 - 10.1016/j.celrep.2014.04.014

    DO - 10.1016/j.celrep.2014.04.014

    M3 - Article

    VL - 7

    SP - 999

    EP - 1008

    JO - Cell Reports

    T2 - Cell Reports

    JF - Cell Reports

    SN - 2211-1247

    IS - 4

    ER -