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  • MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations | Science Translational Medicine
    Oncology University of Torino Candiolo Torino 10060 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Livio Trusolino Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia FPO IRCCS Candiolo Torino 10060 Italy Department of Oncology University of Torino Candiolo Torino 10060 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alex A Adjei Roswell Park Cancer Institute Buffalo NY 14263 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Clara Montagut Medical Oncology Department Hospital del Mar Barcelona 08003 Spain Cancer Research Program FIMIM Hospital del Mar Medical Research Institute Hospital del Mar Barcelona 08003 Spain Find this author on Google Scholar Find this author on PubMed Search for this author on this site Federica Di Nicolantonio Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia FPO IRCCS Candiolo Torino 10060 Italy Department of Oncology University of Torino Candiolo Torino 10060 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rachel Nering Merrimack Pharmaceuticals Inc Cambridge MA 02139 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alberto Bardelli Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia FPO IRCCS Candiolo Torino 10060 Italy Department of Oncology University of Torino Candiolo Torino 10060 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF Article Information vol 8 no 324 324ra14 DOI http dx doi org 10 1126 scitranslmed aad5640 PubMed 26843189 Published By American Association for the Advancement of Science Print ISSN 1946 6234 Online ISSN 1946 6242 History Received for publication 3 October 2015 Accepted for publication 8 January 2016 Copyright Usage Copyright 2016 American Association for the Advancement of Science Author Information Sabrina Arena 1 2 3 Giulia Siravegna 1 3 Benedetta Mussolin 1 Jeffrey D Kearns 4 Beni B Wolf 4 Sandra Misale 1 Luca Lazzari 1 3 Andrea Bertotti 1 3 Livio Trusolino 1 3 Alex A Adjei 5 Clara Montagut 6 7 Federica Di Nicolantonio 1 3 Rachel Nering 4 and Alberto Bardelli 1 3 1 Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia FPO IRCCS Candiolo Torino 10060 Italy 2 FIRC Institute of Molecular Oncology IFOM Milano 20139 Italy 3 Department of Oncology University of Torino Candiolo Torino 10060 Italy 4 Merrimack Pharmaceuticals Inc Cambridge MA 02139 USA 5 Roswell Park Cancer Institute Buffalo NY 14263 USA 6 Medical Oncology Department Hospital del Mar Barcelona 08003 Spain 7 Cancer Research Program FIMIM Hospital del Mar Medical Research Institute Hospital del Mar Barcelona 08003 Spain Corresponding author E mail sabrina arena at ircc it S A alberto bardelli at unito it A Bardelli Present address Blueprint Medicines Cambridge MA 02139 USA Present address Massachusetts General Hospital Cancer

    Original URL path: http://stm.sciencemag.org/content/8/324/324ra14.article-info (2016-02-10)
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  • MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations | Science Translational Medicine
    on Google Scholar Find this author on PubMed Search for this author on this site Andrea Bertotti Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia FPO IRCCS Candiolo Torino 10060 Italy Department of Oncology University of Torino Candiolo Torino 10060 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Livio Trusolino Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia FPO IRCCS Candiolo Torino 10060 Italy Department of Oncology University of Torino Candiolo Torino 10060 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alex A Adjei Roswell Park Cancer Institute Buffalo NY 14263 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Clara Montagut Medical Oncology Department Hospital del Mar Barcelona 08003 Spain Cancer Research Program FIMIM Hospital del Mar Medical Research Institute Hospital del Mar Barcelona 08003 Spain Find this author on Google Scholar Find this author on PubMed Search for this author on this site Federica Di Nicolantonio Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia FPO IRCCS Candiolo Torino 10060 Italy Department of Oncology University of Torino Candiolo Torino 10060 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rachel Nering Merrimack Pharmaceuticals Inc Cambridge MA 02139 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alberto Bardelli Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia FPO IRCCS Candiolo Torino 10060 Italy Department of Oncology University of Torino Candiolo Torino 10060 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF Submit a Response to This Article Compose eLetter Title Contents More information about text formats Plain text Plain text No HTML tags allowed Web page addresses and e mail addresses turn into links automatically Lines and paragraphs break automatically Upload Tables and Figures Attach tables e g doc and figures jpg gif tif by choosing the desired file and then uploading them below Add a new file Upload Files must be less than 100 MB Allowed file types doc jpg jpeg gif tif pdf File names can only contain the following characters A Z a z 0 9 Author Information Contributors First name and middle name First or given name e g Peter Last Name Your last or family name e g MacMoody Email Your email address e g higgs boson gmail com Role Occupation Your role and or occupation e g Orthopedic Surgeon Affiliation Your organization or institution if applicable e g Royal Free Hospital Add another contributor optional Statement of Competing Interests Competing interests Yes No Please describe the competing interests Highwire Comment Subject Apath Vertical Tabs Submit No eLetters have been published for this article View Full Text Science Translational Medicine Vol 8

    Original URL path: http://stm.sciencemag.org/content/8/324/324ra14.e-letters (2016-02-10)
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  • 4099 http stm sciencemag org content 8 324 324ra14 short 4100 http stm sciencemag org content 8 324 324ra14 full AB Monoclonal antibodies against the epidermal growth factor receptor EGFR which drives cancer growth are frequently used in colorectal cancer Unfortunately the cancers commonly develop drug resistant mutations and the monoclonal antibodies become ineffective To overcome this problem Arena et al used an oligoclonal mixture of monoclonal antibodies called MM 151 which binds multiple parts of the EGFR molecule at once so that the cancer cannot develop resistance by mutating one site at a time The authors demonstrated that this approach is effective in both preclinical models and patients who were resistant to other anti EGFR therapies paving the way for further clinical development of the oligoclonal antibody The anti epidermal growth factor receptor EGFR antibodies cetuximab and panitumumab are used to treat RAS wild type colorectal cancers CRCs but their efficacy is limited by the emergence of acquired drug resistance After EGFR blockade about 20 of CRCs develop mutations in the EGFR extracellular domain ECD that impair antibody binding and are associated with clinical relapse We hypothesized that EGFR ECD resistant variants could be targeted by the recently developed

    Original URL path: http://stm.sciencemag.org/highwire/citation/199579/medlars (2016-02-10)
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  • 8 IS 324 SP 324ra14 OP 324ra14 DO 10 1126 scitranslmed aad5640 UL http stm sciencemag org content 8 324 324ra14 abstract AB Monoclonal antibodies against the epidermal growth factor receptor EGFR which drives cancer growth are frequently used in colorectal cancer Unfortunately the cancers commonly develop drug resistant mutations and the monoclonal antibodies become ineffective To overcome this problem Arena et al used an oligoclonal mixture of monoclonal antibodies called MM 151 which binds multiple parts of the EGFR molecule at once so that the cancer cannot develop resistance by mutating one site at a time The authors demonstrated that this approach is effective in both preclinical models and patients who were resistant to other anti EGFR therapies paving the way for further clinical development of the oligoclonal antibody The anti epidermal growth factor receptor EGFR antibodies cetuximab and panitumumab are used to treat RAS wild type colorectal cancers CRCs but their efficacy is limited by the emergence of acquired drug resistance After EGFR blockade about 20 of CRCs develop mutations in the EGFR extracellular domain ECD that impair antibody binding and are associated with clinical relapse We hypothesized that EGFR ECD resistant variants could be targeted by the

    Original URL path: http://stm.sciencemag.org/highwire/citation/199579/refworks (2016-02-10)
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  • IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies | Science Translational Medicine
    this author on this site Paolo M Comoglio Department of Oncology University of Torino Medical School 10060 Candiolo Torino Italy Molecular Clinical Oncology Candiolo Cancer Institute FPO IRCCS 10060 Candiolo Torino Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Enzo Medico Department of Oncology University of Torino Medical School 10060 Candiolo Torino Italy Oncogenomics Candiolo Cancer Institute FPO IRCCS 10060 Candiolo Torino Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sabine Tejpar University Hospital Gasthuisberg 3000 Leuven Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eva Budinská Institute of Biostatistics and Analyses Masaryk University 611 37 Brno Czech Republic Regional Center of Applied Molecular Oncology Masaryk Memorial Cancer Institute 656 53 Brno Czech Republic Find this author on Google Scholar Find this author on PubMed Search for this author on this site Livio Trusolino Department of Oncology University of Torino Medical School 10060 Candiolo Torino Italy Translational Cancer Medicine Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia FPO Istituto di Ricovero e Cura a Carattere Scientifico IRCCS 10060 Candiolo Torino Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrea Bertotti Department of Oncology University of Torino Medical School 10060 Candiolo Torino Italy Translational Cancer Medicine Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia FPO Istituto di Ricovero e Cura a Carattere Scientifico IRCCS 10060 Candiolo Torino Italy National Institute of Biostructures and Biosystems 00136 Rome Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the abstract View Full Text As a service to the community AAAS Science has made this article free with registration Username Enter your Sciencemag org username Password Enter the password that accompanies your username Forgot your username or password Log in Register for Free Join Subscribe Recommend a subscription to your library Help for librarians Abstract Among patients with colorectal cancer who benefit from therapy targeted to the epidermal growth factor receptor EGFR stable disease SD occurs more frequently than massive regressions Exploring the mechanisms of this incomplete sensitivity to devise more efficacious treatments will likely improve patients outcomes We tested therapies tailored around hypothesis generating molecular features in patient derived xenografts xenopatients which originated from 125 independent samples that did not harbor established resistance conferring mutations Samples from xenopatients that responded to cetuximab an anti EGFR agent with disease stabilization displayed high levels of EGFR family ligands and receptors indicating high EGFR pathway activity Five of 21 SD models 23 8 characterized by particularly high expression of EGFR and EGFR family members regressed after intensified EGFR blockade by cetuximab and a small molecule inhibitor In addition a subset of cases in which enhanced EGFR inhibition was unproductive 6

    Original URL path: http://stm.sciencemag.org/content/7/272/272ra12 (2016-02-10)
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  • Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer | Science Translational Medicine
    Torino 10060 Candiolo Torino Italy Institute for Cancer Research and Treatment 10060 Candiolo Torino Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alberto Bardelli Department of Oncology University of Torino 10060 Candiolo Torino Italy Institute for Cancer Research and Treatment 10060 Candiolo Torino Italy Italian Foundation for Cancer Research Institute of Molecular Oncology 20139 Milano Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the abstract View Full Text As a service to the community AAAS Science has made this article free with registration Username Enter your Sciencemag org username Password Enter the password that accompanies your username Forgot your username or password Log in Register for Free Join Subscribe Recommend a subscription to your library Help for librarians Abstract Colorectal cancers CRCs that are sensitive to the anti epidermal growth factor receptor EGFR antibodies cetuximab or panitumumab almost always develop resistance within several months of initiating therapy We report the emergence of polyclonal KRAS NRAS and BRAF mutations in CRC cells with acquired resistance to EGFR blockade Regardless of the genetic alterations resistant cells consistently displayed mitogen activated protein kinase kinase MEK and extracellular signal regulated kinase ERK activation which persisted after EGFR blockade Inhibition of MEK1 2 alone failed to impair the growth of resistant cells in vitro and in vivo An RNA interference screen demonstrated that suppression of EGFR together with silencing of MEK1 2 was required to hamper the proliferation of resistant cells Indeed concomitant pharmacological blockade of MEK and EGFR induced prolonged ERK inhibition and severely impaired the growth of resistant tumor cells Heterogeneous and concomitant mutations in KRAS and NRAS were also detected in plasma samples from patients who developed resistance to anti EGFR antibodies A mouse xenotransplant from a CRC patient who responded and subsequently relapsed upon EGFR therapy showed exquisite sensitivity to combinatorial treatment with MEK and EGFR inhibitors Collectively these results identify genetically distinct mechanisms that mediate secondary resistance to anti EGFR therapies all of which reactivate ERK signaling These observations provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with targeted agents We propose that MEK inhibitors in combination with cetuximab or panitumumab should be tested in CRC patients who become refractory to anti EGFR therapies Copyright 2014 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol 6 Issue 224 19 February 2014 Table of Contents Article Tools Email Thank you for your interest in spreading the word about Science Translational Medicine NOTE We only request your email address so that the person you are recommending the page to knows that you wanted them to see it and that it is not junk mail We do not capture any email address Your Email Your Name Send To Enter multiple addresses on separate lines or separate them

    Original URL path: http://stm.sciencemag.org/content/6/224/224ra26 (2016-02-10)
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  • Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer | Science Translational Medicine
    this author on this site Maria E Arcila Memorial Sloan Kettering Cancer Center Weill Cornell Medical College New York NY 10065 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ross A Soo Cancer Science Institute of Singapore and National University Cancer Institute National University of Singapore Singapore 117599 Singapore Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matthew Meyerson Dana Farber Cancer Institute Harvard Medical School Boston MA 02215 USA Broad Institute Massachusetts Institute of Technology and Harvard Medical School Boston MA 02142 USA Brigham and Women s Hospital Harvard Medical School Boston MA 02115 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael J Eck Dana Farber Cancer Institute Harvard Medical School Boston MA 02215 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Susumu S Kobayashi Beth Israel Deaconess Medical Center Harvard Medical School Boston MA 02215 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel B Costa Beth Israel Deaconess Medical Center Harvard Medical School Boston MA 02215 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the abstract View Full Text As a service to the community AAAS Science has made this article free with registration Username Enter your Sciencemag org username Password Enter the password that accompanies your username Forgot your username or password Log in Register for Free Join Subscribe Recommend a subscription to your library Help for librarians This article has a correction Please see Is corrected by February 26 2014 Abstract Epidermal growth factor receptor EGFR gene mutations G719X exon 19 deletions insertions L858R and L861Q predict favorable responses to EGFR tyrosine kinase inhibitors TKIs in advanced non small cell lung cancer NSCLC However EGFR exon 20 insertion mutations 10 of all EGFR mutations are generally associated with insensitivity to available TKIs gefitinib erlotinib and afatinib The basis of this primary resistance is poorly understood We studied a broad subset of exon 20 insertion mutations comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients and found that most are resistant to EGFR TKIs The crystal structure of a representative TKI insensitive mutant D770 N771insNPG reveals an unaltered adenosine triphosphate binding pocket and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation Unlike EGFR L858R D770 N771insNPG activates EGFR without increasing its affinity for EGFR TKIs Unexpectedly we find that EGFR A763 Y764insFQEA is highly sensitive to EGFR TKIs in vitro and patients whose NSCLCs harbor this mutation respond to erlotinib Analysis of the A763 Y764insFQEA mutant indicates that the inserted residues shift the

    Original URL path: http://stm.sciencemag.org/content/5/216/216ra177 (2016-02-10)
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  • Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab | Science Translational Medicine
    Treatment in all patients is limited eventually by the development of acquired resistance but little is known about the underlying mechanism Here we show that activation of ERBB2 signaling in cell lines either through ERBB2 amplification or through heregulin up regulation leads to persistent extracellular signal regulated kinase 1 2 signaling and consequently to cetuximab resistance Inhibition of ERBB2 or disruption of ERBB2 ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo A subset of colorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab based therapy has ERBB2 amplification or high levels of circulating heregulin Collectively these findings identify two distinct resistance mechanisms both of which promote aberrant ERBB2 signaling that mediate cetuximab resistance Moreover these results suggest that ERBB2 inhibitors in combination with cetuximab represent a rational therapeutic strategy that should be assessed in patients with cetuximab resistant cancers Footnotes These authors contributed equally to this work Citation K Yonesaka K Zejnullahu I Okamoto T Satoh F Cappuzzo J Souglakos D Ercan A Rogers M Roncalli M Takeda Y Fujisaka J Philips T Shimizu O Maenishi Y Cho J Sun A Destro K Taira K Takeda T Okabe J Swanson H Itoh M Takada E Lifshits K Okuno J A Engelman R A Shivdasani K Nishio M Fukuoka M Varella Garcia K Nakagawa P A Jänne Activation of ERBB2 Signaling Causes Resistance to the EGFR Directed Therapeutic Antibody Cetuximab Sci Transl Med 3 99ra86 2011 Copyright 2011 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol 3 Issue 99 07 September 2011 Table of Contents Article Tools Email Thank you for your interest in spreading the word about Science Translational Medicine NOTE We only request your email address so that the person you are recommending the page to knows that you wanted them to see it and that it is not junk mail We do not capture any email address Your Email Your Name Send To Enter multiple addresses on separate lines or separate them with commas You are going to email the following Activation of ERBB2 Signaling Causes Resistance to the EGFR Directed Therapeutic Antibody Cetuximab Message Subject Your Name has forwarded a page to you from Science Translational Medicine Message Body Your Name thought you would like to see this page from the Science Translational Medicine web site Your Personal Message Send Message Download Powerpoint Print Save to my folders User Name Password Remember my user name password Submit Alerts Please log in to add an alert for this article Username Enter your Sciencemag org username Password Enter the password that accompanies your username Log in Request Permissions Citation tools Activation of ERBB2 Signaling Causes Resistance to the EGFR Directed Therapeutic Antibody Cetuximab By Kimio Yonesaka Kreshnik Zejnullahu Isamu Okamoto Taroh Satoh Federico Cappuzzo John Souglakos Dalia Ercan Andrew Rogers Massimo Roncalli Masayuki Takeda Yasuhito Fujisaka Juliet Philips Toshio Shimizu Osamu Maenishi Yonggon Cho Jason Sun Annarita Destro Koichi Taira Koji Takeda Takafumi Okabe Jeffrey Swanson Hiroyuki

    Original URL path: http://stm.sciencemag.org/content/3/99/99ra86 (2016-02-10)
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