Supplementary Figure S6 from mTOR Inhibition via Displacement of Phosphatidic Acid Induces Enhanced Cytotoxicity Specifically in Cancer Cells

Nguyen, Tra-Ly; Nokin, Marie-Julie; Egorov, Maxim; Tomé, Mercedes; Bodineau, Clément; Di Primo, Carmelo; Minder, Lætitia; Wdzieczak-Bakala, Joanna; Garcia-Alvarez, Maria Concepcion; Bignon, Jérôme; Thoison, Odile; Delpech, Bernard; Surpateanu, Georgiana; Frapart, Yves-Michel; Peyrot, Fabienne; Abbas, Kahina; Terés, Silvia; Evrard, Serge; Khatib, Abdel-Majid; Soubeyran, Pierre; Iorga, Bogdan I.; Durán, Raúl V.; Collin, Pascal

doi:10.1158/0008-5472.22419347.v1

00085472can180232-sup-195990_2_supp_4896722_pc09tx.pdf (461.25 kB)

Supplementary Figure S6 from mTOR Inhibition via Displacement of Phosphatidic Acid Induces Enhanced Cytotoxicity Specifically in Cancer Cells

journal contribution

posted on 2023-03-31, 02:01 authored by Tra-Ly Nguyen, Marie-Julie Nokin, Maxim Egorov, Mercedes Tomé, Clément Bodineau, Carmelo Di Primo, Lætitia Minder, Joanna Wdzieczak-Bakala, Maria Concepcion Garcia-Alvarez, Jérôme Bignon, Odile Thoison, Bernard Delpech, Georgiana Surpateanu, Yves-Michel Frapart, Fabienne Peyrot, Kahina Abbas, Silvia Terés, Serge Evrard, Abdel-Majid Khatib, Pierre Soubeyran, Bogdan I. Iorga, Raúl V. Durán, Pascal Collin

The file contains supplementary results showing that inhibition of mTORC1 by ICSN3250 is responsible for its cytotoxicity in cancer cells.

History

ARTICLE 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.