Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma

PI3K/AKT/mTOR通路 次黄嘌呤 嘌呤代谢 癌症研究 生物 代谢组学 蛋白激酶B 生物化学 化学 药理学 信号转导 生物信息学
作者
Hideki Makinoshima,Shigeki Umemura,Ayako Suzuki,Hiroki Nakanishi,Ami Maruyama,Hibiki Udagawa,Sachiyo Mimaki,Shingo Matsumoto,Seiji Niho,Genichiro Ishii,Masahiro Tsuboi,Atsushi Ochiai,Hiroyasu Esumi,Takehiko Sasaki,Kōichi Goto,Katsuya Tsuchihara
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:78 (9): 2179-2190 被引量:35
标识
DOI:10.1158/0008-5472.can-17-2109
摘要

Abstract 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 metabolomics as a tool for finding novel therapeutic biomarkers. Cancer Res; 78(9); 2179–90. ©2018 AACR.

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
Teio完成签到,获得积分10
刚刚
YMAO关注了科研通微信公众号
1秒前
实验耗材发布了新的文献求助10
2秒前
2秒前
3秒前
邵大帅发布了新的文献求助10
3秒前
科研通AI2S应助无限莫言采纳,获得10
3秒前
3秒前
科研大佬发布了新的文献求助10
4秒前
mushini完成签到,获得积分10
4秒前
JeaClear应助Parsifal采纳,获得50
4秒前
小强发布了新的文献求助10
4秒前
自由又夏发布了新的文献求助10
4秒前
传奇3应助自觉馒头采纳,获得10
4秒前
5秒前
Mrdu发布了新的文献求助10
5秒前
李爱国应助汎影采纳,获得10
5秒前
Logan发布了新的文献求助10
6秒前
luanzh完成签到,获得积分10
6秒前
hsvxvk发布了新的文献求助50
6秒前
孤独元容完成签到 ,获得积分10
6秒前
房秋发布了新的文献求助10
6秒前
蓝胖子发布了新的文献求助10
7秒前
lylyzhl完成签到,获得积分20
7秒前
mint完成签到,获得积分10
8秒前
小李发布了新的文献求助10
8秒前
9秒前
seal发布了新的文献求助10
9秒前
ggbang发布了新的文献求助10
10秒前
Maggie发布了新的文献求助10
10秒前
自觉的凛完成签到,获得积分10
10秒前
11秒前
臭臭的香菇应助小陈采纳,获得30
11秒前
11秒前
善学以致用应助lish采纳,获得10
11秒前
SciGPT应助达啦崩啦采纳,获得10
12秒前
嘟嘟嘟完成签到 ,获得积分10
12秒前
隐形曼青应助jekin采纳,获得10
12秒前
六件套发布了新的文献求助10
13秒前
靓丽念薇发布了新的文献求助10
14秒前
高分求助中
歯科矯正学 第7版(或第5版) 1004
SIS-ISO/IEC TS 27100:2024 Information technology — Cybersecurity — Overview and concepts (ISO/IEC TS 27100:2020, IDT)(Swedish Standard) 1000
Smart but Scattered: The Revolutionary Executive Skills Approach to Helping Kids Reach Their Potential (第二版) 1000
Semiconductor Process Reliability in Practice 720
GROUP-THEORY AND POLARIZATION ALGEBRA 500
Mesopotamian divination texts : conversing with the gods : sources from the first millennium BCE 500
Days of Transition. The Parsi Death Rituals(2011) 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3232097
求助须知:如何正确求助?哪些是违规求助? 2879078
关于积分的说明 8208910
捐赠科研通 2546486
什么是DOI,文献DOI怎么找? 1376123
科研通“疑难数据库(出版商)”最低求助积分说明 647536
邀请新用户注册赠送积分活动 622709