PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition.
PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition.
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DOI：
10.1016/j.ccell.2016.06.004
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发表时间：
2016-08-08
期刊：
影响因子：
50.3
通讯作者：
Scaltriti M
中科院分区：
文献类型：
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作者：
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
PIK 3CA编码PI 3 K的p110α亚基，在乳腺癌中经常发生突变和致癌。PI 3 K α抑制剂处于临床开发阶段，尽管具有良好的早期临床活性，但患者中的固有耐药性很常见。我们之前曾报道过，用PI 3 K α抑制剂治疗后残留的下游mTORC 1活性会导致对这些药物的耐药性。然而，这种表型的机制尚未完全了解。在这里，我们表明，在对PI 3 K α抑制耐药的癌细胞中，PDK 1阻断恢复了对这些疗法的敏感性。由PDK 1激活的SGK 1通过直接磷酸化和抑制TSC 2来维持残留的mTORC 1活性。靶向PDK 1或SGK 1可阻止mTORC 1活化，恢复PI 3 K α抑制在耐药细胞中的抗肿瘤作用。PDK 1-SGK 1轴可在PI 3 K/AKT抑制后维持mTORC 1活性SGK 1直接磷酸化TSC 2，导致mTORC 1活化靶向PDK 1使PIK 3CA突变细胞对PI 3 K α抑制敏感Castel et al.显示PDK 1激活SGK 1磷酸化并抑制TSC 2，有助于维持mTORC 1活性和PIK 3CA突变癌细胞对PI 3 K α抑制的抗性。靶向PDK 1或SGK 1可恢复这些耐药癌细胞对PI 3 K α抑制的敏感性。
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. The PDK1-SGK1 axis can sustain mTORC1 activity upon PI3K/AKT suppression SGK1 directly phosphorylates TSC2, resulting in mTORC1 activation Targeting PDK1 sensitizes PIK3CA-mutant cells to PI3Kα inhibition Castel et al. show that PDK1 activates SGK1 to phosphorylate and inhibit TSC2, contributing to maintenance of mTORC1 activity and resistance of PIK3CA-mutant cancer cells to PI3Kα inhibition. Targeting either PDK1 or SGK1 restores the sensitivity of these resistant cancer cells to PI3Kα inhibition.