Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition
Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition
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DOI：
10.1016/j.celrep.2020.01.080
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发表时间：
2020-02-25
期刊：
影响因子：
8.8
通讯作者：
Kamphorst, Jurre J.
中科院分区：
文献类型：
--
作者：
Michalopoulou, Evdokia;Auciello, Francesca R.;Kamphorst, Jurre J.
胰腺导管腺癌(PDAC)的特点是在KRAS中有一种几乎普遍的突变。此外，肿瘤抑制基因PTEN在大约10%的患者中丢失，在小鼠模型中，这显著加速了肿瘤的进展。虽然致癌的KRAS和磷脂酰肌醇3-激酶(PI3K)各自导致不同的代谢表型，但它们如何协同促进肿瘤的代谢变化和相关性仍不清楚。我们发现，在KRAS驱动的小鼠PDAC细胞中，Pten的丢失强烈地增强了mTOR信号和巨噬细胞吞噬。蛋白质清除通过挽救AKT丝氨酸473的磷酸化从而减轻对mTOR抑制的敏感性，从而减轻细胞增殖。联合抑制mTOR和内化蛋白的溶酶体处理可消除巨噬细胞吞噬介导的耐药性。我们的结果表明，mTORC2而不是mTORC1是蛋白质清除的重要调节因子，蛋白质介导的抗性可以解释在某些遗传背景下mTOR抑制剂缺乏有效性的原因。同时抑制mTOR和蛋白质清除可能是一种有价值的治疗方法。
Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in similar to 10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of Pten strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach.