MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations.

Arena, Sabrina; Siravegna, Giulia; Mussolin, Benedetta; Kearns, Jeffrey  D.; Wolf, Beni  B.; Misale, Sandra; Lazzari, Luca; Bertotti, Andrea; Trusolino, Livio; Adjei, Alex  A.; Montagut Viladot, Clara; Di  Nicolantonio, Federica; Nering, Rachel; Bardelli, Alberto

MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations.

Mostra el registre complet Registre parcial de l'ítem

dc.contributor.author Arena, Sabrinaca
dc.contributor.author Siravegna, Giuliaca
dc.contributor.author Mussolin, Benedettaca
dc.contributor.author Kearns, Jeffrey D.ca
dc.contributor.author Wolf, Beni B.ca
dc.contributor.author Misale, Sandraca
dc.contributor.author Lazzari, Lucaca
dc.contributor.author Bertotti, Andreaca
dc.contributor.author Trusolino, Livioca
dc.contributor.author Adjei, Alex A.ca
dc.contributor.author Montagut Viladot, Claraca
dc.contributor.author Di Nicolantonio, Federicaca
dc.contributor.author Nering, Rachelca
dc.contributor.author Bardelli, Albertoca
dc.date.accessioned 2016-04-27T10:13:36Z
dc.date.available 2016-04-27T10:13:36Z
dc.date.issued 2016
dc.description.abstract 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 oligoclonal antibody MM-151 that binds multiple regions of the EGFR ECD. MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade. These data provide molecular rationale for the clinical use of MM-151 in patients who become resistant to cetuximab or panitumumab as a result of EGFR ECD mutations.ca
dc.description.sponsorship This study was supported by 5 per mille 2009 MIUR—from Fondazione Piemontese per la Ricerca sul Cancro— ONLUS ‘Farmacogenomica’ to FDN); Associazione Italiana per la Ricerca sul Cancro (AIRC) MFAG (11349 to FDN). European Community’s Seventh Framework Programme under grant agreement no. 602901 MErCuRIC (A.Bardelli and F.D.N.); IMI contract n. 115749 CANCER-ID (A.Bardelli); AIRC 2010 Special Program Molecular Clinical Oncology 5 per mille, Project n. 9970 (A.Bardelli); Fondazione/nPiemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2010 e 2011 Ministero della Salute (A.Bardelli and F.D.N..); Ministero dell’Istruzione, dell’Università e della Ricerca - progetto PRIN 2010-2011 (A.Bardelli)
dc.format.mimetype application/pdfca
dc.identifier.citation Arena S, Siravegna G, Mussolin B, Kearns JD, Wolf BB, Misale S. et al. MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations. Sci Transl Med. 2016 Feb 3;8(324):324ra14. doi: 10.1126/scitranslmed.aad5640.ca
dc.identifier.doi http://dx.doi.org/10.1126/scitranslmed.aad5640
dc.identifier.issn 1946-6234
dc.identifier.uri http://hdl.handle.net/10230/26180
dc.language.iso engca
dc.publisher American Association for the Advancement of Scienceca
dc.relation.ispartof Science Translational Medicine. 2016 Feb 3;8(324):324ra14
dc.relation.projectID info:eu-repo/grantAgreement/FP7/602901
dc.relation.projectID info:eu-repo/grantAgreement/FP7/115749
dc.rights This is tha autor's version of the work. It is postered here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on 2016 Feb 3;8(324):324ra14. doi: 10.1126/scitranslmed.aad5640.ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.subject.other Còlon -- Càncer -- Aspectes genèticsca
dc.title MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations.ca
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/acceptedVersionca

Col·leccions

Articles (Hospital del Mar Research Institute)
Documents OpenAIRE (Open Access Infrastructure for Research in Europe)