GLI1 Blockade Potentiates the Antitumor Activity of PI3K Antagonists in Lung Squamous Cell Carcinoma.
GLI1 Blockade Potentiates the Antitumor Activity of PI3K Antagonists in Lung Squamous Cell Carcinoma.
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DOI：
10.1158/0008-5472.can-16-3315
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发表时间：
2017-08-15
期刊：
影响因子：
11.2
通讯作者：
Kim J
中科院分区：
文献类型：
--
作者：
Kasiri S;Shao C;Chen B;Wilson AN;Yenerall P;Timmons BC;Girard L;Tian H;Behrens C;Wistuba II;Gazdar AF;Kim J
肺鳞状细胞癌 (SCC) 与吸烟密切相关，由于缺乏 FDA 批准的靶向药物，主要采用传统的细胞毒性化疗进行治疗。在这里，我们将 Hedgehog 通路转录因子 GLI1 确定为肺 SCC 的关键驱动因素。对人类肺癌数据集的分析表明，GLI1 mRNA 在人肺鳞状细胞癌中高表达，预示着不良预后。在人肺 SCC 细胞系中抑制 GLI1 可抑制培养物和体内肿瘤细胞的克隆形成和增殖。添加 SHH 配体、SMO 拮抗剂或其他 Hedgehog 通路激动剂不会影响肺 SCC 细胞中的 GLI1 表达。然而，GLI1 表达受到 PI3K 和 MAPK 通路抑制或激活的调节。此外，通过拮抗 GLI1 和 PI3K，可以减弱携带 PI3K 基因 PIK3CA 扩增的 SCC 的体内生长。因此，与单药 PI3K 拮抗剂的人体试验最新结果相反，针对 PI3K-mTOR 通路和 GLI1 的组合治疗策略可能会为 PI3K 通路依赖性癌症带来有效的结果。
Lung squamous cell carcinoma (SCC), strongly associated with smoking, is treated primarily with traditional cytotoxic chemotherapy due to a lack of FDA-approved targeted agents available. Here we identify the Hedgehog pathway transcription factor GLI1 as a critical driver of lung SCC. Analysis of human lung cancer datasets showed that GLI1 mRNA was highly expressed in human lung SCC and portended a poor prognosis. Inhibition of GLI1 in human lung SCC cell lines suppressed tumor cell clonogenicity and proliferation in culture and in vivo. Addition of SHH ligand, SMO antagonists, or other Hedgehog pathway agonists did not affect GLI1 expression in lung SCC cells. However, GLI1 expression was modulated by either inhibition or activation of the PI3K and MAPK pathways. Furthermore, in vivo growth of SCC harboring amplifications of the PI3K gene PIK3CA was attenuated by antagonizing GLI1 and PI3K. Thus, a combinatorial therapeutic strategy that targets the PI3K-mTOR pathway and GLI1 may lead to effective outcomes for PI3K pathway-dependent cancers, in contrast to recent results of human trials with single-agent PI3K antagonists.