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Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers

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Listed:
  • Sandra Misale

    (Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
    FIRC Institute of Molecular Oncology (IFOM))

  • Ivana Bozic

    (Program for Evolutionary Dynamics, Harvard University
    Harvard University)

  • Jingshan Tong

    (University of Pittsburgh Cancer Institute
    University of Pittsburgh School of Medicine)

  • Ashley Peraza-Penton

    (Duke University)

  • Alice Lallo

    (Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
    University of Torino)

  • Federica Baldi

    (Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
    University of Torino)

  • Kevin H. Lin

    (Duke University)

  • Mauro Truini

    (Niguarda Cancer Center, Ospedale Niguarda Ca’ Granda)

  • Livio Trusolino

    (Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
    University of Torino)

  • Andrea Bertotti

    (Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
    University of Torino)

  • Federica Di Nicolantonio

    (Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
    University of Torino)

  • Martin A. Nowak

    (Program for Evolutionary Dynamics, Harvard University
    Harvard University
    Harvard University)

  • Lin Zhang

    (University of Pittsburgh Cancer Institute
    University of Pittsburgh School of Medicine)

  • Kris C. Wood

    (Duke University)

  • Alberto Bardelli

    (Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
    University of Torino)

Abstract

Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance. In patient-derived xenografts, EGFR-MEK combination prevents the development of resistance. We employ mathematical modelling to provide a quantitative understanding of the dynamics of response and resistance to these single and combination therapies. Mechanistically, we find that the EGFR-MEK Combo blockade triggers Bcl-2 and Mcl-1 downregulation and initiates apoptosis. These results provide the rationale for clinical trials aimed at preventing rather than intercepting resistance.

Suggested Citation

  • Sandra Misale & Ivana Bozic & Jingshan Tong & Ashley Peraza-Penton & Alice Lallo & Federica Baldi & Kevin H. Lin & Mauro Truini & Livio Trusolino & Andrea Bertotti & Federica Di Nicolantonio & Martin , 2015. "Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9305
    DOI: 10.1038/ncomms9305
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