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FOXM1持续表达导致对PI3Kα抑制剂的抵抗

作者:葡京赌城真人发布时间:2020-09-26 18:58

本期文章:《癌细胞》:Online/在线发表

2020年9月24日出版的《癌细胞》杂志在线发表英国剑桥大学Kevin M. Brindle、Susana Ros课题组的最新研究。他们利用代谢物成像发现在雌激素受体(ER)+乳腺癌中持续表达的FOXM1介导了对PI3Kα抑制剂的抗性。

研究人员发现药物治疗后持续表达的FOXM1是ER+乳腺癌中PI3Kα抑制剂抗性的生物标记物。FOXM1促进乳酸脱氢酶(LDH)的表达,但不诱导己糖激酶2(HK-II)的表达。因此,可以通过使用MRI检测丙酮酸和乳酸之间LDH催化产生的超极化13C标记而非通过HK-II介导的葡萄糖类似物2-脱氧-2- [18F]氟脱氧葡萄糖的正电子发射断层扫描测量来表征下游代谢变化。使用这种成像方法对乳腺癌的治疗反应进行快速评估可以帮助鉴定对PI3Kα抑制有反应的患者,并设计药物组合以抵消耐药性的出现。

PIK3CA编码PI3Kα的同分异构体,是ER阳性乳腺癌患者中最常见的致癌基因。临床上使用同工型选择PI3K的抑制剂,但固有和获得性耐药限制了它们的实际应用。研发针对这些患者的更有效药物需要可预测的生物标志物。

附:英文原文

 

Title:Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer

 

Author:Susana Ros Alan J. Wright Paula D'Santos Alejandra Bruna Carlos Caldas Kevin M. Brindle

 

Issue&Volume:September 24, 2020

 

Abstract: PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER+ breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized 13C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[18F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance.

 

DOI:https://doi.org/10.1016/j.ccell.2020.08.016

 

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30427-X

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx

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