Synergistic action of a RAF inhibitor and a dual PI3K/mTOR inhibitor in thyroid cancer.
Synergistic action of a RAF inhibitor and a dual PI3K/mTOR inhibitor in thyroid cancer.
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DOI：
10.1158/1078-0432.ccr-11-0933
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发表时间：
2011-10-15
期刊：
影响因子：
--
通讯作者：
Ball DW
中科院分区：
文献类型：
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作者：
Jin N;Jiang T;Rosen DM;Nelkin BD;Ball DW
在甲状腺癌临床试验中，靶向VEGF受体和RET以及其他激酶的药物已经导致部分反应，但很少有完全或持久的反应。RAF-MEK-ERK和PI3K-AKT-mTOR信号通路在分化型和髓样甲状腺癌（DTC和MTC）中经常被激活，可能为这些疾病提供治疗靶点。我们在具有明确遗传背景的甲状腺癌临床前模型中测试了一种针对RAF、PI3K和mTOR，以及VEGFR2和RET的新型药物组合。RAF265是一种对VEGFR2具有活性的atp竞争性泛raf抑制剂，BEZ-235是一种对Torc1和Torc2也具有活性的PI3K抑制剂，他们在一组甲状腺癌细胞中单独和联合进行了测试。我们在异种移植模型中测试了RAF265和BEZ-235的激酶抑制、生长抑制和细胞周期改变，以及信号靶点和肿瘤生长的抑制。这两种药物都能有效抑制ERK和PI3K通路中的激酶靶点。此外，RAF265对RETC634W具有显著的RET抑制活性（IC50为25 ~ 50 nM）。该组合强烈抑制RAS、BRAF、PTEN和RET突变的DTC和MTC细胞系的增殖。对B-CPAP （BRAFV600E）和TT细胞（RETC634W）显示协同作用。两种药物联合使用可显著抑制CAL62 （KRASG12R/G12R）和TT异种移植物的生长，彻底抑制ERK和PI3K通路信号传导。联合阻断ERK和PI3K信号通路可有效抑制难治性甲状腺癌关键基因型临床前模型的生长。这些靶点和治疗方法在DTC和MTC中都有进一步发展的希望。
In thyroid cancer clinical trials, agents targeting VEGF receptors and RET, among other kinases, have led to partial responses but few complete or durable responses. The RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways are frequently activated in differentiated and medullary thyroid cancer (DTC and MTC) and may provide therapeutic targets for these diseases. We tested a novel drug combination targeting RAF, PI3K and mTOR, plus VEGFR2 and RET, in thyroid cancer preclinical models with defined genetic backgrounds. RAF265, an ATP-competitive pan-RAF inhibitor active against VEGFR2, and BEZ-235, a PI3K inhibitor also active against Torc1 and Torc2, were tested alone and in combination in a panel of thyroid cancer lines. We tested RAF265 and BEZ-235 for kinase inhibition, growth inhibition and cell cycle alterations, and inhibition of signaling targets and tumor growth in xenograft models. Both drugs potently inhibited their kinase targets in the ERK and PI3K pathways. In addition, RAF265 had significant RET inhibitory activity (IC50 25–50 nM for RETC634W). The combination strongly inhibited proliferation of DTC and MTC lines with mutations in RAS, BRAF, PTEN, and RET. Synergy was demonstrated for B-CPAP (BRAFV600E) and TT cells (RETC634W). The combination of both drugs significantly inhibited growth of CAL62 (KRASG12R/G12R) and TT xenografts, thoroughly inhibiting ERK and PI3K pathway signaling. Combined blockade of ERK and PI3K signaling potently inhibits growth in preclinical models representing the key genotypes seen in refractory thyroid cancer. These targets and therapies are promising for further development in both DTC and MTC.