HIF-mediated Suppression of DEPTOR Confers Resistance to mTOR Kinase Inhibition in Renal Cancer
Hong Doan,
Alexander Parsons,
Shruthi Devkumar,
Jogitha Selvarajah,
Francesc Miralles,
Veronica A. Carroll
Affiliations
Hong Doan
Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, UK
Alexander Parsons
Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, UK
Shruthi Devkumar
Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, UK; Centre for Biomedical Education, Institute of Medical and Biomedical Education, St George's, University of London, London SW17 0RE, UK
Jogitha Selvarajah
Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, UK; Centre for Biomedical Education, Institute of Medical and Biomedical Education, St George's, University of London, London SW17 0RE, UK
Francesc Miralles
Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, UK; Centre for Biomedical Education, Institute of Medical and Biomedical Education, St George's, University of London, London SW17 0RE, UK
Veronica A. Carroll
Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, UK; Centre for Biomedical Education, Institute of Medical and Biomedical Education, St George's, University of London, London SW17 0RE, UK; Corresponding author
Summary: Mechanistic target of rapamycin (mTOR) is a fundamental regulator of cell growth, proliferation, and metabolism. mTOR is activated in renal cancer and accelerates tumor progression. Here, we report that the mTOR inhibitor, DEP domain-containing mTOR-interacting protein (DEPTOR), is strikingly suppressed in clear cell renal cell carcinoma (ccRCC) tumors and cell lines. We demonstrate that DEPTOR is repressed by both hypoxia-inducible factors, HIF-1 and HIF-2, which occurs through activation of the HIF-target gene and transcriptional repressor, BHLHe40/DEC1/Stra13. Restoration of DEPTOR- and CRISPR/Cas9-mediated knockout experiments demonstrate that DEPTOR is growth inhibitory in ccRCC. Furthermore, loss of DEPTOR confers resistance to second-generation mTOR kinase inhibitors through deregulated mTORC1 feedback to IRS-2/PI3K/Akt. This work reveals a hitherto unknown mechanism of resistance to mTOR kinase targeted therapy that is mediated by HIF-dependent reprograming of mTOR/DEPTOR networks and suggests that restoration of DEPTOR in ccRCC will confer sensitivity to mTOR kinase therapeutics. : Biological Sciences; Cancer; Cell Biology Subject Areas: Biological Sciences, Cancer, Cell Biology
