Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer.
Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer.
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DOI：
10.1158/1078-0432.ccr-14-1591
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发表时间：
2015-01-15
期刊：
影响因子：
--
通讯作者：
Bardeesy N
中科院分区：
文献类型：
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作者：
Alagesan B;Contino G;Guimaraes AR;Corcoran RB;Deshpande V;Wojtkiewicz GR;Hezel AF;Wong KK;Loda M;Weissleder R;Benes CH;Engelman J;Bardeesy N
胰腺导管腺癌（PDAC）的治疗需要改进的治疗方法。由于双重MEK和PI3K抑制目前正在用于PDAC患者的临床试验，我们试图通过体外药物筛选和基因工程小鼠模型（GEMMs）来测试PDAC中这些途径的联合靶向效果。我们对500个人类癌细胞系（包括46个PDAC系）进行了高通量筛选，检测其对50种临床相关化合物的敏感性，包括MEK和PI3K抑制剂。我们在krasg12d驱动的GEMM中测试了屏幕上最受欢迎的MEK1/2抑制剂AZD-6244单独或与PI3K抑制剂BKM-120或GDC-0941联合的疗效，该GEMM重现了人类PDAC的组织发病机制。体外筛选显示PDAC细胞系对单药治疗相对耐药。对MEK1/2抑制剂AZD-6244的反应谱是一个异常值，在PDAC中显示出最高的选择性功效。虽然MEK单独抑制主要是细胞抑制，但与PI3K抑制剂（BKM-120或GDC-0941）联合时可诱导细胞凋亡。在PDAC GEMM试验中，与单药或载体对照相比，联合用药在预防方面延迟了肿瘤形成，在治疗晚期肿瘤时延长了生存期，尽管没有观察到持久的反应。我们的研究指出了MEK和PI3K信号在PDAC发病机制中的重要作用，并提示双重靶向这些途径可能对一些PDAC患者有益。
Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being employed in clinical trials for PDAC patients, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMMs). We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically-relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD-6244, for efficacy alone or in combination with the PI3K inhibitors, BKM-120 or GDC-0941, in a KRASG12D-driven GEMM that recapitulates the histopathogenesis of human PDAC. In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD-6244, was an outlier, showing the highest selective efficacy in PDAC. While MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM-120 or GDC-0941). When tested in a PDAC GEMM and compared to the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed. Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some PDAC patients.