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Targeting mTOR pathway inhibits tumor growth in different molecular subtypes of triple-negative breast cancers

2016; Impact Journals LLC; Volume: 7; Issue: 30 Linguagem: Inglês

10.18632/oncotarget.10195

1949-2553

Rana Hatem, Rania El Botty, Sophie Château‐Joubert, Jean‐Luc Servely, Dalila Labiod, Ludmilla de Plater, Franck Assayag, Florence Coussy, Céline Callens, Sophie Vacher, Fabien Reyal, Sabina Cosulich, Véronique Dièras, Ivan Bièche, Elisabetta Marangoni,

Microtubule and mitosis dynamics

// Rana Hatem 1, 2 , Rania El Botty 3 , Sophie Chateau-Joubert 4 , Jean-Luc Servely 4, 5 , Dalila Labiod 3 , Ludmilla de Plater 3 , Franck Assayag 3 , Florence Coussy 1, 3, 8 , Céline Callens 1 , Sophie Vacher 1 , Fabien Reyal 3, 6 , Sabina Cosulich 7 , Véronique Diéras 8 , Ivan Bièche 1, 9, * , Elisabetta Marangoni 3, * 1 Genetics Department, Institut Curie, PSL Research University, Paris, France 2 Faculty of Pharmacy, Aleppo University, Aleppo, Syria 3 Translational Research Department, Institut Curie, PSL Research University, Paris, France 4 BioPôle Alfort, National Veterinary School of Alfort, Maisons Alfort, France 5 INRA, PHASE Department, Paris, France 6 Surgery Department, Institut Curie, PSL Research University, Paris, France 7 AstraZeneca R&D Cambridge, CRUK Cambridge Institute, Cambridge, UK 8 Medical Oncology Department, Institut Curie, PSL Research University, Paris, France 9 EA7331, University of Paris Descartes, Paris, France * These authors have contributed equally to this work Correspondence to: Elisabetta Marangoni, email: elisabetta.marangoni@curie.fr Keywords: TNBC, mTOR, PI3K pathway, PDX Received: January 25, 2016 Accepted: June 09, 2016 Published: June 21, 2016 ABSTRACT Triple-negative breast cancers (TNBC) are characterized by frequent alterations in the PI3K/AKT/mTOR signaling pathway. In this study, we analyzed PI3K pathway activation in 67 patient-derived xenografts (PDX) of breast cancer and investigated the anti-tumor activity of the mTOR inhibitor everolimus in 15 TNBC PDX with different expression and mutational status of PI3K pathway markers. Expression of the tumor suppressors PTEN and INPP4B was lost in 55% and 76% of TNBC PDX, respectively, while mutations in PIK3CA and AKT1 genes were rare. In 7 PDX treatment with everolimus resulted in a tumor growth inhibition higher than 50%, while 8 models were classified as low responder or resistant. Basal-like, LAR (Luminal AR), mesenchymal and HER2-enriched tumors were present in both responder and resistant groups, suggesting that tumor response to everolimus is not restricted to a specific TNBC subtype. Analysis of treated tumors showed a correlation between tumor response and post-treatment phosphorylation of AKT, increased in responder PDX, while PI3K pathway markers at baseline were not sufficient to predict everolimus response. In conclusion, targeting mTOR decreased tumor growth in 7 out of 15 TNBC PDX tested. Response to everolimus occurred in different TNBC subtypes and was associated with post-treatment increase of P-AKT.