Inhibition of mTOR downregulates expression of DNA repair proteins and is highly efficient against BRCA2-mutated breast cancer in combination to PARP inhibition
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Rania El Botty1, Florence Coussy1,2,3, Rana Hatem2, Franck Assayag1, Sophie Chateau-Joubert4, Jean-Luc Servely4,5, Sophie Leboucher6, Charles Fouillade7, Sophie Vacher2, Bérengère Ouine1, Aurélie Cartier1, Leanne de Koning1, Paul Cottu3, Ivan Bièche2 and Elisabetta Marangoni1
1Institut Curie, PSL Research University, Translational Research Department, 75005 Paris, France
2Genetics Department, Institut Curie, PSL Research University, 75005 Paris, France
3Medical Oncology Department, Institut Curie, PSL Research University, 75005 Paris, France
4BioPôle Alfort, Ecole Nationale Vétérinaire d’Alfort, 94700 Maisons Alforts, France
5INRA, PHASE Department, UMR3306, 75338 Paris, France
6Institut Curie, PSL Research University, UMR3306, 91405 Orsay, France
7Institut Curie, PSL Research University, Inserm U 612, Centre Universitaire, 91405 Orsay, France
Elisabetta Marangoni, email: email@example.com
Keywords: BRCA2; breast cancer; mTOR; DNA repair; PDX
Received: April 27, 2017 Accepted: June 01, 2018 Published: July 03, 2018
Breast cancer is a complex disease in which each patient could present several genetic alterations that are therapeutically relevant in cancers. Here we explored the therapeutic benefit of combining PARP and mTOR inhibitors in a context of DNA repair deficiency and PI3K pathway activation.
The combination of everolimus and olaparib was tested in BRCA2-mutated patient-derived xenografts (PDX) carrying alterations in the PI3K/AKT/mTOR pathway. An RPPA analysis of different signalling pathways was performed in untreated and treated xenografts.
Everolimus and olaparib showed marked anti-tumor activities in the monotherapy setting and high efficacy when given in combination with 100% of mice showing tumor regressions. The fraction of P-H2AX positive cells was increased in both monotherapy arms and strongly increased in the combination setting. Everolimus given as monotherapy resulted in downregulation of different proteins involved in DNA damage repair, including FANCD2, RAD50 and SUV39H1. In the combination setting, expression of these proteins was almost completely abolished, suggesting convergence of PARP and mTOR in downregulation of DNA damage repair components.
In conclusion, our results suggest that combining mTOR and DNA repair inhibition could be a successful strategy to treat a subset of breast cancer with BRCA2 mutation and alterations in the PI3K/AKT/mTOR pathway.
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