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

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 A. Nowak, Lin Zhang, Kris C. Wood and Alberto Bardelli ()
Additional contact information
Sandra Misale: Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
Ivana Bozic: Program for Evolutionary Dynamics, Harvard University
Jingshan Tong: University of Pittsburgh Cancer Institute
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)
Federica Baldi: Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
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)
Andrea Bertotti: Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
Federica Di Nicolantonio: Candiolo Cancer Institute — Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
Martin A. Nowak: Program for Evolutionary Dynamics, Harvard University
Lin Zhang: University of Pittsburgh Cancer Institute
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)

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9305

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