The mTOR is a key regulator of cell growth that integrates growth factor signaling and nutrient availability and is a downstream effector of oncogenic receptor tyrosine kinases (RTK) and PI3K/Akt signaling. Thus, activating mTOR mutations would be expected to enhance growth in many tumor types. However, tumor sequencing data have shown that mTOR mutations are enriched only in renal clear cell carcinoma, a clinically hypervascular tumor unlikely to be constrained by nutrient availability. To further define this cancer-type–specific restriction, we studied activating mutations in mTOR. All mTOR mutants tested enhanced growth in a cell-type agnostic manner under nutrient-replete conditions but were detrimental to cell survival in nutrient-poor conditions. Consistently, analysis of tumor data demonstrated that oncogenic mutations in the nutrient-sensing arm of the mTOR pathway display a similar phenotype and were exceedingly rare in human cancers of all types. Together, these data suggest that maintaining the ability to turn off mTOR signaling in response to changing nutrient availability is retained in most naturally occurring tumors. Significance: This study suggests that cells need to inactivate mTOR to survive nutrient stress, which could explain the rarity of mTOR mutations and the limited clinical activity of mTOR inhibitors in cancer.

中文翻译：

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在营养不良的条件下激活 mTOR 突变是有害的

mTOR 是细胞生长的关键调节因子，整合了生长因子信号传导和营养可用性，并且是致癌受体酪氨酸激酶 (RTK) 和 PI3K/Akt 信号传导的下游效应器。因此，激活 mTOR 突变有望促进许多肿瘤类型的生长。然而，肿瘤测序数据表明，mTOR 突变仅在肾透明细胞癌中富集，这是一种临床上血管丰富的肿瘤，不太可能受到营养可用性的限制。为了进一步定义这种癌症类型特异性限制，我们研究了 mTOR 的激活突变。所有 mTOR 突变体在营养充足的条件下都以与细胞类型无关的方式增强了生长，但在营养不良的条件下不利于细胞存活。对肿瘤数据的分析一致表明，mTOR 通路营养感应臂中的致癌突变表现出相似的表型，并且在所有类型的人类癌症中极为罕见。总之，这些数据表明，在大多数自然发生的肿瘤中保留了关闭 mTOR 信号传导以响应营养可用性变化的能力。意义：这项研究表明，细胞需要使 mTOR 失活才能在营养应激下生存，这可以解释 mTOR 突变的罕见性以及 mTOR 抑制剂在癌症中的临床活性有限。