2. Academic Validation
  3. mTOR Inhibition via Displacement of Phosphatidic Acid Induces Enhanced Cytotoxicity Specifically in Cancer Cells

mTOR Inhibition via Displacement of Phosphatidic Acid Induces Enhanced Cytotoxicity Specifically in Cancer Cells

  • Cancer Res. 2018 Sep 15;78(18):5384-5397. doi: 10.1158/0008-5472.CAN-18-0232.
Tra-Ly Nguyen 1,  Marie-Julie Nokin 1 2,  Maxim Egorov 3 4,  Mercedes Tomé 5,  Clément Bodineau 1,  Carmelo Di Primo 6,  Lætitia Minder 7,  Joanna Wdzieczak-Bakala 4,  Maria Concepcion Garcia-Alvarez 4,  Jérôme Bignon 4,  Odile Thoison 4,  Bernard Delpech 4,  Georgiana Surpateanu 4,  Yves-Michel Frapart 8,  Fabienne Peyrot 8 9,  Kahina Abbas 8,  Silvia Terés 1,  Serge Evrard 10,  Abdel-Majid Khatib 5,  Pierre Soubeyran 11,  Bogdan I Iorga 12,  Raúl V Durán 13,  Pascal Collin 4 8 14
Affiliations

Affiliations

  • 1 Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France.
  • 2 Metastasis Research Laboratory, GIGA-Cancer, University of Liège (ULiège), Liège, Belgium.
  • 3 ATLANTHERA, Cedex, France.
  • 4 Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Gif-sur-Yvette, France.
  • 5 Laboratoire de l'Angiogénèse et du Microenvironnement des Cancers, INSERM U1029, Université de Bordeaux, Allée Geoffroy Saint Hilaire, Bâtiment, Pessac, France.
  • 6 Université de Bordeaux, Laboratoire ARNA, Bordeaux, France; INSERM U1212, CNRS UMR 5320, Institut Européen de Chimie et Biologie, CNRS UMS3033/INSERMUS001, Pessac, France.
  • 7 Université de Bordeaux, CNRS UMS3033/INSERM US001, Institut Européen de Chimie et Biologie, Pessac, France.
  • 8 Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • 9 Ecole Supérieure du Professorat et de l'Education de l'Académie de Paris, Sorbonne Université, Paris, France.
  • 10 Institut Bergonié, Digestive Tumours Unit, Université de Bordeaux, Bordeaux, France.
  • 11 Institut Bergonié, INSERM U1218, Université de Bordeaux, Bordeaux, France.
  • 12 Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Gif-sur-Yvette, France. raul.duran@inserm.fr bogdan.iorga@cnrs.fr.
  • 13 Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France. raul.duran@inserm.fr bogdan.iorga@cnrs.fr.
  • 14 Université Paris Diderot, UFR Odontologie, Paris, France.
PMID: 30054335 DOI: 10.1158/0008-5472.CAN-18-0232
Abstract

The mTOR is a central regulator of cell growth and is highly activated in Cancer cells to allow rapid tumor growth. The use of mTOR inhibitors as Anticancer therapy has been approved for some types of tumors, albeit with modest results. We recently reported the synthesis of ICSN3250, a halitulin analogue with enhanced cytotoxicity. We report here that ICSN3250 is a specific mTOR Inhibitor that operates through a mechanism distinct from those described for previous mTOR inhibitors. ICSN3250 competed with and displaced phosphatidic acid from the FRB domain in mTOR, thus preventing mTOR activation and leading to cytotoxicity. Docking and molecular dynamics simulations evidenced not only the high conformational plasticity of the FRB domain, but also the specific interactions of both ICSN3250 and phosphatidic acid with the FRB domain in mTOR. Furthermore, ICSN3250 toxicity was shown to act specifically in Cancer cells, as noncancer cells showed up to 100-fold less sensitivity to ICSN3250, in contrast to Other mTOR inhibitors that did not show selectivity. Thus, our results define ICSN3250 as a new class of mTOR inhibitors that specifically targets Cancer cells.Significance: ICSN3250 defines a new class of mTORC1 inhibitors that displaces phosphatidic acid at the FRB domain of mTOR, inducing cell death specifically in Cancer cells but not in noncancer cells. Cancer Res; 78(18); 5384-97. ©2018 AACR.

Figures
Products