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|Ref Type||Journal Article|
|Authors||Castel P, Ellis H, Bago R, Toska E, Razavi P, Carmona FJ, Kannan S, Verma CS, Dickler M, Chandarlapaty S, Brogi E, Alessi DR, Baselga J, Scaltriti M|
|Title||PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition.|
|Date||2016 Aug 08|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA mutant||breast cancer||sensitive||Alpelisib + GSK2334470||Preclinical - Cell line xenograft||Actionable||In a preclinical study, GSK2334470 resensitized Alpelisib (BYL719)-resistant breast cancer cell lines harboring PIK3CA mutations to Alpelisib (BYL719) in culture and in cell line xenograft models (PMID: 27451907).||27451907|