Research Papers:

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

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

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Oncotarget. 2016; 7:48206-48219. https://doi.org/10.18632/oncotarget.10195

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Rana Hatem1,2, Rania El Botty3, Sophie Chateau-Joubert4, Jean-Luc Servely4,5, Dalila Labiod3, Ludmilla de Plater3, Franck Assayag3, Florence Coussy1,3,8, Céline Callens1, Sophie Vacher1, Fabien Reyal3,6, Sabina Cosulich7, Véronique Diéras8, Ivan Bièche1,9,*, Elisabetta Marangoni3,*

1Genetics Department, Institut Curie, PSL Research University, Paris, France

2Faculty of Pharmacy, Aleppo University, Aleppo, Syria

3Translational Research Department, Institut Curie, PSL Research University, Paris, France

4BioPôle Alfort, National Veterinary School of Alfort, Maisons Alfort, France

5INRA, PHASE Department, Paris, France

6Surgery Department, Institut Curie, PSL Research University, Paris, France

7AstraZeneca R&D Cambridge, CRUK Cambridge Institute, Cambridge, UK

8Medical Oncology Department, Institut Curie, PSL Research University, Paris, France

9EA7331, University of Paris Descartes, Paris, France

*These authors have contributed equally to this work

Correspondence to:

Elisabetta Marangoni, email: [email protected]

Keywords: TNBC, mTOR, PI3K pathway, PDX

Received: January 25, 2016    Accepted: June 09, 2016    Published: June 21, 2016


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.

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