PI3K/mTOR 抑制剂 PF-04691502 的抗肿瘤活性在诱导头颈癌人异种移植和小鼠基因敲除模型中的野生型 TP53 时增强。
PI3K/mTOR inhibitor PF-04691502 antitumor activity is enhanced with induction of wild-type TP53 in human xenograft and murine knockout models of head and neck cancer.
机构信息
Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892, USA.
出版信息
Clin Cancer Res. 2013 Jul 15;19(14):3808-19. doi: 10.1158/1078-0432.CCR-12-2716. Epub 2013 May 2.
PURPOSE
Phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway activation is often associated with altered expression or mutations of PIK3CA, TP53/p73, PTEN, and TGF-β receptors (TGFBR) in head and neck squamous cell carcinomas (HNSCC). However, little is known about how these alterations affect response to PI3K/mTOR-targeted agents.
EXPERIMENTAL DESIGN
In this preclinical study, PI3K/Akt/mTOR signaling was characterized in nine HNSCC (UM-SCC) cell lines and human oral keratinocytes. We investigated the molecular and anticancer effects of dual PI3K/mTOR inhibitor PF-04691502(PF-502) in UM-SCC expressing PIK3CA with decreased wild-type TP53, mutant TP53-/+ mutantTGFBR2, and in HNSCC of a conditional Pten/Tgfbr1 double knockout mouse model displaying PI3K/Akt/mTOR activation.
RESULTS
UM-SCC showed increased PIK3CA expression and Akt/mTOR activation, and PF-502 inhibited PI3K/mTORC1/2 targets. In human HNSCC expressing PIK3CA and decreased wtTP53 and p73, PF-502 reciprocally enhanced TP53/p73 expression and growth inhibition, which was partially reversible by p53 inhibitor pifithrin-α. Most UM-SCC with wtTP53 exhibited a lower IC50 than those with mtTP53 status. PF-502 blocked growth in G0-G1 and increased apoptotic sub-G0 DNA. PF-502 suppressed tumorigenesis and showed combinatorial activity with radiation in a wild-type TP53 UM-SCC xenograft model. PF-502 also significantly delayed HNSCC tumorigenesis and prolonged survival of Pten/Tgfbr1-deficient mice. Significant inhibition of p-Akt, p-4EBP1, p-S6, and Ki67, as well as increased p53 and TUNEL were observed in tumor specimens.
CONCLUSIONS
PI3K-mTOR inhibition can enhance TP53/p73 expression and significantly inhibit tumor growth alone or when combined with radiation in HNSCC with wild-type TP53. PIK3CA, TP53/p73, PTEN, and TGF-β alterations are potential modifiers of response and merit investigation in future clinical trials with PI3K-mTOR inhibitors.
目的
磷酸肌醇 3-激酶（PI3K）/哺乳动物雷帕霉素靶蛋白（mTOR）通路的激活常与头颈部鳞状细胞癌（HNSCC）中 PIK3CA、TP53/p73、PTEN 和 TGF-β受体（TGFBR）的表达改变或突变有关。然而，对于这些改变如何影响对 PI3K/mTOR 靶向药物的反应，人们知之甚少。
实验设计
在这项临床前研究中，我们在 9 种 HNSCC（UM-SCC）细胞系和人口腔角质形成细胞中对 PI3K/Akt/mTOR 信号通路进行了表征。我们研究了双重 PI3K/mTOR 抑制剂 PF-04691502（PF-502）在表达 PIK3CA 且野生型 TP53 减少、突变型 TP53-/+突变型 TGFBR2 的 UM-SCC 中的分子和抗癌作用，以及在显示 PI3K/Akt/mTOR 激活的条件性 Pten/Tgfbr1 双重敲除小鼠模型中的 HNSCC 中的作用。
结果
UM-SCC 显示 PIK3CA 表达增加和 Akt/mTOR 激活，PF-502 抑制 PI3K/mTORC1/2 靶标。在表达 PIK3CA 且野生型 TP53 和 p73 减少的人 HNSCC 中，PF-502 可反向增强 TP53/p73 表达和生长抑制，p53 抑制剂 pifithrin-α可部分逆转这一作用。大多数具有野生型 TP53 的 UM-SCC 的 IC50 低于具有突变型 TP53 状态的 IC50。PF-502 阻断 G0-G1 期的生长并增加凋亡性亚 G0 DNA。PF-502 在野生型 TP53 UM-SCC 异种移植模型中抑制肿瘤发生并与放射联合具有组合活性。PF-502 还显著延迟 HNSCC 肿瘤发生并延长 Pten/Tgfbr1 缺陷小鼠的存活期。在肿瘤标本中观察到 p-Akt、p-4EBP1、p-S6 和 Ki67 的显著抑制以及 p53 和 TUNEL 的增加。
结论
在具有野生型 TP53 的 HNSCC 中，PI3K-mTOR 抑制可单独或与放射联合增强 TP53/p73 表达，并显著抑制肿瘤生长。PI3K、TP53/p73、PTEN 和 TGF-β 的改变可能是反应的潜在调节剂，值得在未来的 PI3K-mTOR 抑制剂临床试验中进行研究。
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