Point mutations of the mTOR-RHEB pathway in renal cell carcinoma.
Point mutations of the mTOR-RHEB pathway in renal cell carcinoma.
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DOI：
10.18632/oncotarget.4963
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发表时间：
2015-07-20
期刊：
影响因子：
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通讯作者：
Sudarshan S
中科院分区：
文献类型：
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作者：
Ghosh AP;Marshall CB;Coric T;Shim EH;Kirkman R;Ballestas ME;Ikura M;Bjornsti MA;Sudarshan S
mTOR（雷帕霉素的机制靶点）轴的畸变在癌症中经常被报道。利用公开的肿瘤基因组测序数据，我们在透明细胞肾细胞癌（ccRCC）患者中鉴定了MTOR及其上游调节因子RHEB（脑中富集的Ras同源物）的几个点突变，透明细胞肾细胞癌是肾癌最常见的组织学类型。有趣的是，我们在肾细胞癌中mTOR的FAT（FRAP-ATM-TTRAP）结构域中发现了一组显著的超活化突变，导致mTORC 1和mTORC 2活性增加，并导致细胞增殖增加。几个FAT结构域突变体显示出DEPTOR（含有mTOR相互作用蛋白的DEP结构域）结合减少，而这些突变的子集显示出负调节因子PRAS 40（富含脯氨酸的AKT底物40）结合改变。我们还确定了ccRCC患者中RHEB的复发性突变，导致mTORC 1活性增加。该RHEB突变体的体外表征显示，该突变体对TSC 2（恶性硬化2）GAP（GTP酶激活蛋白）活性显示出相当大的抗性，尽管其与TSC 2的相互作用保持不变。MTOR的FAT结构域和RHEB中的突变仍然对雷帕霉素敏感，尽管其中几个突变在以临床相关剂量的雷帕霉素治疗后表现出残留的mTOR激酶活性。总的来说，我们的数据表明，mTOR通路中的点突变可能通过多种不同的机制导致下游mTOR过度激活，从而赋予肿瘤细胞增殖优势。
Aberrations in the mTOR (mechanistic target of rapamycin) axis are frequently reported in cancer. Using publicly available tumor genome sequencing data, we identified several point mutations in MTOR and its upstream regulator RHEB (Ras homolog enriched in brain) in patients with clear cell renal cell carcinoma (ccRCC), the most common histology of kidney cancer. Interestingly, we found a prominent cluster of hyperactivating mutations in the FAT (FRAP-ATM-TTRAP) domain of mTOR in renal cell carcinoma that led to an increase in both mTORC1 and mTORC2 activities and led to an increased proliferation of cells. Several of the FAT domain mutants demonstrated a decreased binding of DEPTOR (DEP domain containing mTOR-interacting protein), while a subset of these mutations showed altered binding of the negative regulator PRAS40 (proline rich AKT substrate 40). We also identified a recurrent mutation in RHEB in ccRCC patients that leads to an increase in mTORC1 activity. In vitro characterization of this RHEB mutation revealed that this mutant showed considerable resistance to TSC2 (Tuberous Sclerosis 2) GAP (GTPase activating protein) activity, though its interaction with TSC2 remained unaltered. Mutations in the FAT domain of MTOR and in RHEB remained sensitive to rapamycin, though several of these mutations demonstrated residual mTOR kinase activity after treatment with rapamycin at clinically relevant doses. Overall, our data suggests that point mutations in the mTOR pathway may lead to downstream mTOR hyperactivation through multiple different mechanisms to confer a proliferative advantage to a tumor cell.