Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma
Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma
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DOI：
10.1158/0008-5472.can-17-2109
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发表时间：
2018-05-01
期刊：
影响因子：
11.2
通讯作者：
Tsuchihara, Katsuya
中科院分区：
文献类型：
--
作者：
Makinoshima, Hideki;Umemura, Shigeki;Tsuchihara, Katsuya
全面的基因组分析显示，PI 3 K/AKT/mTOR通路是小细胞肺癌（SCLC）的可行治疗靶点。然而，尚未确定用于鉴定可能从该途径抑制剂中获益的患者的生物标志物。在这里，我们表明代谢特征决定了SCLC细胞对PI 3 K/mTOR双重抑制剂gedatolisib的敏感性。大量磷脂酰脂质分析显示，特定的磷脂酰肌醇（3，4，5）-三磷酸（PIP 3）亚种脂质产物PIP 3（38：4）在评估对PI 3 K/mTOR双重抑制剂的敏感性方面具有预测性。值得注意的是，我们发现更高量的嘌呤相关水性代谢物，如次黄嘌呤，这是SCLC生物学的特征，导致对PI 3 K通路抑制的抗性。此外，编码次黄嘌呤磷酸核糖基转移酶1（嘌呤补救途径的关键组分）的mRNA水平在对吉它托利西敏感或耐药的SCLC细胞之间存在显著差异。此外，与嘌呤代谢物的互补可以逆转通常对gedatolisib敏感的SCLC细胞中PI 3 K通路靶向的脆弱性。这些结果表明，PI 3 K途径抑制剂的耐药机制是通过激活嘌呤补救途径介导的，为核苷酸生物合成提供嘌呤资源。代谢组学是寻找SCLC治疗中新的治疗生物标志物的有力方法。意义：这些发现确定了决定SCLC对PI 3 K通路抑制的敏感性的特征，并支持代谢组学作为寻找新的治疗生物标志物的工具。(C)2018年AACR。
Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here, we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product PIP3 (38: 4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1, a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment.Significance: These findings identify features that determine sensitivity of SCLC to PI3K pathway inhibition and support meta-bolomics as a tool for finding novel therapeutic biomarkers. (C) 2018 AACR.