Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2013 Jul 15;19(14):3808-19. doi: 10.1158/1078-0432.CCR-12-2716. Epub 2013 May 2.
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.
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.
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.
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.
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。
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。
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。
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。
