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.
Highlights
The serine/threonine kinase mTOR is a master regulator of cell growth, highly conserved among eukaryotes [1, 2]. mTOR is organized in two structurally and functionally different complexes: the rapamycin-sensitive mTORC1 and the rapamycin-insensitive mTORC2. mTORC1 is mostly activated by the presence of amino acids, by growth factors, by the bioenergetics status of the cell, and by oxygen availability
Our results indicated that ICSN3250 inhibited mTORC1 by following an unprecedented mechanism that involved its competition with phosphatidic acid (PA) at the FRB domain of mTOR to overcome the tuberous sclerosis complex (TSC)-negative regulation of mTORC1
Some other pathways, such as PI3K, ERK, and mTORC2, showed an increase in the phosphorylation of their respective downstream targets. This increase would be in agreement with a specific inhibition of mTORC1 pathway and the subsequent release of the negative feedback loop that leads to PI3K reactivation [13]
Summary
The serine/threonine kinase mTOR is a master regulator of cell growth, highly conserved among eukaryotes [1, 2]. mTOR is organized in two structurally and functionally different complexes: the rapamycin-sensitive mTORC1 (mTOR complex 1) and the rapamycin-insensitive mTORC2 (mTOR complex 2; refs. 3–6). mTORC1 is mostly activated by the presence of amino acids, by growth factors, by the bioenergetics status of the cell, and by oxygen availability. The serine/threonine kinase mTOR is a master regulator of cell growth, highly conserved among eukaryotes [1, 2]. MTORC1 is mostly activated by the presence of amino acids, by growth factors, by the bioenergetics status of the cell, and by oxygen availability. In the control of mTORC1 by growth factors, the tuberous sclerosis complex (TSC) and the mTORC1 coactivator Rheb play a crucial role [7, 8]. One of the mechanisms by which the TSC/Rheb pathway controls mTORC1 involves the production of phosphatidic acid (PA), which binds directly to mTOR at the FRB domain and activates mTORC1 downstream of TSC/Rheb. Several reasons have been invoked for these modest results in the clinics, including the reactivation of a negative feedback loop downstream of mTORC1 that activates the PI3K pathway [13], the absence of mTORC2
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