Identification of a new molecular target to prevent metastatic dissemination of breast cancer cells exposed to cl-CD95L

4^th World Congress on Cancer Science & Therapy

October 20-22, 2014 DoubleTree by Hilton Hotel Chicago-North Shore Conference Center, USA

Patrick Legembre, Amélie Fouqué, Olivier Delalande, Mickael Jean, Mac Dinh Hung, Marine Malleter, Hariniaina Rampanarivo and Pierre van de Weghe

Accepted Abstracts: J Cancer Sci Ther

Abstract :

Breast cancers represent a heterogeneous pathology, which can be classified as Triple-negative breast cancers (TNBC), non-TNBC and HER2+. TNBCsare characterized by a negative immunohistochemical staining for estrogen (ER) and progesterone (PR) receptors and human epidermal growth factor-2 (HER2). Metastases and relapsesremain more frequent in TNBC patients than in Non-TNBC women due to the aggressiveness of these tumors and the lack of tailor-made therapeutic treatment options.Therefore, identification of new therapeutic targets for TNBCs is ofcrucial interest. Our group works on the so-called death receptor CD95 known to initiate apoptosis by interacting with its ligand CD95L. CD95L is a transmembrane ligand (m-CD95L) that can be cleaved by metalloproteases. We recently showed that unlike m-CD95L, the naturallyprocessed CD95L (cl-CD95L) is a potent prognostic marker of metastatic dissemination in TNBC women. Furthermore, we demonstratedthat cl-CD95L promotes TNBC cellmigrationthrough induction of an ?unconventional?PI3K/Akt/mTOR signaling pathway. To block this non-apoptotic signaling pathway, we attempted to generate in collaboration with modelers and chemists, an inhibitor of the PI3K/mTOR pathway. From a chromene backbone and multiple rounds of in silico/in vitro and in cellulo drug screening, we identified a molecular lead designated DHM25 that showed a strong anti-tumor activity against breast tumor cells. A large-scale kinase assay against the human kinome revealed that DHM25 turnedout to be a selective and potent mTOR inhibitor. In summary, we have designed and synthesized a potent and covalentmTOR inhibitor that represents a very attractive therapeutic agent to impair CD95-mediated cell motility in TNBC cells and, by doing this, to reduce the risk of metastatic dissemination in these women.