title: Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers.
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.
authors.affiliation: Candiolo Cancer Institute - Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, 10060, Italy.|FIRC Institute of Molecular Oncology (IFOM), Milano 20139, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Misale
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Mathematics, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bozic
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Jingshan
authors.initials: J
authors.lastname: Tong
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Peraza-Penton
authors.affiliation: Candiolo Cancer Institute - Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, 10060, Italy.|University of Torino, Department of Oncology, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Lallo
authors.affiliation: Candiolo Cancer Institute - Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, 10060, Italy.|University of Torino, Department of Oncology, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Baldi
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Lin
authors.affiliation: Division of Pathology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milano, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Truini
authors.affiliation: Candiolo Cancer Institute - Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, 10060, Italy.|University of Torino, Department of Oncology, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.affiliation: Candiolo Cancer Institute - Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, 10060, Italy.|University of Torino, Department of Oncology, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.affiliation: Candiolo Cancer Institute - Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, 10060, Italy.|University of Torino, Department of Oncology, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Federica
authors.identifier: http://orcid.org/0000-0001-9618-2010
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Mathematics, Harvard University, Cambridge, Massachusetts 02138, USA.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Nowak
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Kris C
authors.initials: KC
authors.lastname: Wood
authors.affiliation: Candiolo Cancer Institute - Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino, 10060, Italy.|University of Torino, Department of Oncology, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D000068818:Cetuximab / Q000008:administration & dosage / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009374:Neoplasms, Experimental; D000077544:Panitumumab; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C504459:FILIP1L protein, human; D047908:Intracellular Signaling Peptides and Proteins; D000077544:Panitumumab; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; D000068818:Cetuximab