2026-04-14T02:32:39Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/437872025-12-24T08:38:54Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Sampera Borràs, Aïda, 1990- author Sánchez-Martín, Francisco Javier author Arpí Llucià, Oriol author Visa Turmo, Laura author Iglesias Coma, Mar author Menéndez, Silvia author Gaye, Élisabeth author Dalmases Massegú, Alba, 1982- author Clavé Safont, Sergi author Gelabert-Baldrich, Mariona author Tuxen Poulsen, Thomas author Kragh, Michael author Bellosillo Paricio, Beatriz author Albanell Mestres, Joan author Rovira Guerín, Ana author Rovira Guerín, Ana author Montagut Viladot, Clara author 2020-03-04T08:25:13Z 2019 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. Aparell digestiu -- Càncer -- Tractament HER-family ligands promote acquired resistance to trastuzumab in gastric cancer