PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition

Cancer Cell. 2016 Aug 8;30(2):229-242. doi: 10.1016/j.ccell.2016.06.004.

Pau Castel ¹, Haley Ellis ¹, Ruzica Bago ², Eneda Toska ¹, Pedram Razavi ³, F Javier Carmona ¹, Srinivasaraghavan Kannan ⁴, Chandra S Verma ⁵, Maura Dickler ⁶, Sarat Chandarlapaty ³, Edi Brogi ⁷, Dario R Alessi ², José Baselga ⁸, Maurizio Scaltriti ⁹

Affiliations

1 Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
2 MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland.
3 Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, Suite M2015, New York, NY 10065, USA.
4 Bioinformatics Institute (A(∗)STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
5 Bioinformatics Institute (A(∗)STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
6 Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, Suite M2015, New York, NY 10065, USA.
7 Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
8 Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, Suite M2015, New York, NY 10065, USA. Electronic address: [email protected].
9 Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. Electronic address: [email protected].

PMID: 27451907 DOI: 10.1016/j.ccell.2016.06.004

Abstract

PIK3CA, which encodes the p110α subunit of PI3K, is frequently mutated and oncogenic in breast Cancer. PI3Kα inhibitors are in clinical development and despite promising early clinical activity, intrinsic resistance is frequent among patients. We have previously reported that residual downstream mTORC1 activity upon treatment with PI3Kα inhibitors drives resistance to these agents. However, the mechanism underlying this phenotype is not fully understood. Here we show that in Cancer cells resistant to PI3Kα inhibition, PDK1 blockade restores sensitivity to these therapies. SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2. Targeting either PDK1 or SGK1 prevents mTORC1 activation, restoring the antitumoral effects of PI3Kα inhibition in resistant cells.

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