Data from A Diverse Array of Cancer-Associated <i>MTOR</i> Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity

Abstract

<div>Abstract<p>Genes encoding components of the PI3K–AKT–mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in <i>MTOR</i>, the gene encoding the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 <i>MTOR</i> mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor DEPTOR. mTOR complex 1 (mTORC1) signaling in cells expressing various activating mutations remains sensitive to pharmacologic mTOR inhibition, but is partially resistant to nutrient deprivation. Finally, cancer cell lines with hyperactivating <i>MTOR</i> mutations display heightened sensitivity to rapamycin both in culture and <i>in vivo</i> xenografts, suggesting that such mutations confer mTOR pathway dependency.</p><p><b>Significance:</b> We report that a diverse set of cancer-associated <i>MTOR</i> mutations confer increased mTORC1/2 pathway activity and that cells harboring these mutations are highly sensitive to rapamycin in culture and <i>in vivo</i>. These findings are clinically relevant as the <i>MTOR</i> mutations characterized herein may serve as biomarkers for predicting tumor responses to mTOR inhibitors. <i>Cancer Discov; 4(5); 554–63. ©2014 AACR</i>.</p><p>See related commentary by Rejto and Abraham, p. 513</p><p>This article is highlighted in the In This Issue feature, p. 495</p></div>