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Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs

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dc.contributor.author Blancafort, Adriana
dc.contributor.author Giró Perafita, Ariadna
dc.contributor.author Oliveras, Glòria
dc.contributor.author Palomeras, Sònia
dc.contributor.author Turrado, Carlos
dc.contributor.author Campuzano Larrea, Oscar
dc.contributor.author Carrion Salip, Dolors
dc.contributor.author Massaguer i Vall-llovera, Anna
dc.contributor.author Brugada, Ramon
dc.contributor.author Palafox, Marta
dc.contributor.author Gómez Miragaya, Jorge
dc.contributor.author González Suárez, Eva
dc.contributor.author Puig Miquel, Teresa
dc.date.issued 2015
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/10256/10901
dc.description.abstract Blocking the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of HER2-positive breast carcinoma cells. The hypothesis is that blocking FASN, in combination with anti-HER2 signaling agents, would be an effective antitumor strategy in preclinical HER2+ breast cancer models of trastuzumab and lapatinib resistance. We developed and molecularly characterized in vitro HER2+ models of resistance to trastuzumab (SKTR), lapatinib (SKLR) and both (SKLTR). The cellular interactions of combining anti-FASN polyphenolic compounds (EGCG and the synthetic G28UCM) with anti-HER2 signaling drugs (trastuzumab plus pertuzumab and temsirolimus) were analyzed. Tumor growth inhibition after treatment with EGCG, pertuzumab, temsirolimus or the combination was evaluated in two in vivo orthoxenopatients: one derived from a HER2+ patient and another from a patient who relapsed on trastuzumab and lapatinib-based therapy. SKTR, SKLR and SKLTR showed hyperactivation of EGFR and p-ERK1/2 and PI3KCA mutations. Dual-resistant cells (SKLTR) also showed hyperactivation of HER4 and recovered levels of p-AKT compared with mono-resistant cells. mTOR, p-mTOR and FASN expression remained stable in SKTR, SKLR and SKLTR. In vitro, anti-FASN compounds plus pertuzumab showed synergistic interactions in lapatinib- and dual-resistant cells and improved the results of pertuzumab plus trastuzumab co-treatment. FASN inhibitors combined with temsirolimus displayed the strongest synergistic interactions in resistant cells. In vivo, both orthoxenopatients showed strong response to the antitumor activity of the combination of EGCG with pertuzumab or temsirolimus, without signs of toxicity. We showed that the simultaneous blockade of FASN and HER2 pathways is effective in cells and in breast cancer models refractory to anti-HER2 therapies
dc.format.extent 22 p.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Public Library of Science (PLoS)
dc.relation.isformatof Reproducció digital del document publicat a: http://dx.doi.org/10.1371/journal.pone.0131241
dc.relation.ispartof PLoS One, 2015, vol. 10, núm. 6, p. e0131241
dc.relation.ispartofseries Articles publicats (D-CM)
dc.rights Reconeixement 3.0 Espanya
dc.rights.uri http://creativecommons.org/licenses/by/3.0/es
dc.source Blancafort, Adriana Giró-Perafita, Ariadna Oliveras, Glòria Palomeras, Sònia Turrado, Carlos Campuzano Larrea, Oscar Carrion-Salip, Dolors Massaguer i Vall-llovera, Anna Brugada, Ramon Palafox, Marta Gómez-Miragaya, Jorge González-Suárez, Eva Puig Miquel, Teresa 2015 Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs PLoS One 10 6 e0131241
dc.subject Mama -- Càncer
dc.subject Breast -- Cancer
dc.title Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs
dc.type info:eu-repo/semantics/article
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion
dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0131241


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