HER-family ligands promote acquired resistance to trastuzumab in gastric cancer

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• dc.contributor.author Sampera Borràs, Aïda, 1990-
• dc.contributor.author Sánchez-Martín, Francisco Javier
• dc.contributor.author Arpí Llucià, Oriol
• dc.contributor.author Visa Turmo, Laura
• dc.contributor.author Iglesias Coma, Mar
• dc.contributor.author Menéndez, Silvia
• dc.contributor.author Gaye, Élisabeth
• dc.contributor.author Dalmases Massegú, Alba, 1982-
• dc.contributor.author Clavé Safont, Sergi
• dc.contributor.author Gelabert-Baldrich, Mariona
• dc.contributor.author Tuxen Poulsen, Thomas
• dc.contributor.author Kragh, Michael
• dc.contributor.author Bellosillo Paricio, Beatriz
• dc.contributor.author Albanell Mestres, Joan
• dc.contributor.author Rovira Guerín, Ana
• dc.contributor.author Rovira Guerín, Ana
• dc.contributor.author Montagut Viladot, Clara
• dc.date.accessioned 2020-03-04T08:25:13Z
• dc.date.issued 2019
• dc.description.abstract Despite the clinical benefit of trastuzumab, eventually all HER2-amplified gastric cancer tumors develop drug resistance. We aimed to identify molecular mechanisms of acquired resistance to trastuzumab in gastric cancer by using well-established cell line-based preclinical models, as well as samples from patients with HER2-positive gastric cancer treated with trastuzumab. We studied trastuzumab resistance in NCI-N87 and OE19, two gastric cancer cell lines that overexpress HER2 receptor and are trastuzumab sensitive. Differences at protein, DNA, and RNA levels between the parental and resistant cells were characterized and functional studies were performed. Paired pre- and post-trastuzumab blood and tissue samples from patients with gastric cancer treated with trastuzumab were analyzed. We found that resistant cells were associated with increased activation of MAPK/ERK and PI3K/mTOR pathways driven by SRC activation. Upstream, resistant cells showed increased coexpression of multiple HER-family ligands that allowed for compensatory activation of alternative HER receptors upon HER2 blockade. Simultaneous inhibition of EGFR, HER2, and HER3 by the novel antibody mixture, Pan-HER, effectively reverted trastuzumab resistance in vitro and in vivo Similarly, an increase in HER-family ligands was observed in serum and tumor from patients with gastric cancer after trastuzumab therapy. We propose that trastuzumab resistance in gastric cancer is mediated by HER-family ligand upregulation that allows a compensatory activation of HER receptors and maintains downstream signaling activation despite trastuzumab therapy. Resistance is reverted by simultaneous inhibition of EGFR, HER2, and HER3, thereby revealing a potential therapeutic strategy to overcome trastuzumab resistance in patients with gastric cancer.
• dc.format.mimetype application/pdf
• dc.identifier.citation Sampera A, Sánchez-Martín FJ, Arpí O, Visa L, Iglesias M, Menéndez S et al. HER-family ligands promote acquired resistance to trastuzumab in gastric cancer. Mol Cancer Ther. 2019 Nov;18(11):2135-45. DOI: 10.1158/1535-7163.MCT-19-0455
• dc.identifier.doi http://dx.doi.org/10.1158/1535-7163.MCT-19-0455
• dc.identifier.issn 1535-7163
• dc.identifier.uri http://hdl.handle.net/10230/43787
• dc.language.iso eng
• dc.publisher American Association for Cancer Research (AACR)
• dc.relation.ispartof Molecular Cancer Therapeutics. 2019 Nov;18(11):2135-45
• dc.rights © American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/1535-7163.MCT-19-0455
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Aparell digestiu -- Càncer -- Tractament
• dc.title HER-family ligands promote acquired resistance to trastuzumab in gastric cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion