Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Otolaryngology, Baylor College of Medicine, Houston, Texas.
Clin Cancer Res. 2019 Jun 1;25(11):3329-3340. doi: 10.1158/1078-0432.CCR-18-3276. Epub 2019 Feb 15.
Head and neck squamous cell carcinoma (HNSCC) is driven largely by the loss of tumor suppressor genes, including , but lacks a biomarker-driven targeted therapy. Although the PI3K/mTOR pathway is frequently altered in HNSCC, the disease has modest clinical response rates to PI3K/mTOR inhibitors and lacks validated biomarkers of response. We tested the hypothesis that an unbiased pharmacogenomics approach to PI3K/mTOR pathway inhibitors would identify novel, clinically relevant molecular vulnerabilities in HNSCC with loss of tumor suppressor function. We assessed the degree to which responses to PI3K/mTOR inhibitors are associated with gene mutations in 59 HNSCC cell lines. Apoptosis in drug-sensitive cell lines was confirmed and . NOTCH1 pathway components and PDK1 were manipulated with drugs, gene editing, knockdown, and overexpression.
PI3K/mTOR inhibition caused apoptosis and decreased colony numbers in HNSCC cell lines harboring loss-of-function mutations ( ) and reduced tumor size in subcutaneous and orthotopic xenograft models. In all cell lines, was strongly associated with sensitivity to six PI3K/mTOR inhibitors. NOTCH1 inhibition or knockout increased HNSCC sensitivity to PI3K/mTOR inhibition. PDK1 levels dropped following PI3K/mTOR inhibition in but not HNSCC, and PDK1 overexpression rescued apoptosis in cells. PDK1 and AKT inhibitors together caused apoptosis in HNSCC but had little effect as single agents.
Our findings suggest that predicts response to PI3K/mTOR inhibitors, which may lead to the first biomarker-driven targeted therapy for HNSCC, and that targeting PDK1 sensitizes HNSCC to PI3K/mTOR pathway inhibitors.
头颈部鳞状细胞癌（HNSCC）主要由肿瘤抑制基因丧失驱动，包括 ，但缺乏基于生物标志物的靶向治疗。尽管 PI3K/mTOR 通路在 HNSCC 中经常改变，但该疾病对 PI3K/mTOR 抑制剂的临床反应率较低，并且缺乏反应的验证生物标志物。我们测试了一个假设，即采用无偏倚的药物基因组学方法来研究 PI3K/mTOR 通路抑制剂，将在肿瘤抑制功能丧失的 HNSCC 中确定新的、具有临床相关性的分子脆弱性。我们评估了对 PI3K/mTOR 抑制剂的反应与 59 种 HNSCC 细胞系中的基因突变之间的相关性。在药物敏感细胞系中证实了凋亡，并 。用药物、基因编辑、敲低和过表达来操纵 NOTCH1 通路成分和 PDK1。
PI3K/mTOR 抑制导致携带 功能丧失突变（ ）的 HNSCC 细胞系发生凋亡和集落数量减少，并在皮下和原位异种移植模型中减小肿瘤体积。在所有细胞系中， 与对六种 PI3K/mTOR 抑制剂的敏感性强烈相关。NOTCH1 抑制或敲除增加了 对 PI3K/mTOR 抑制的敏感性。PI3K/mTOR 抑制后， 中的 PDK1 水平下降，但 中的 PDK1 水平没有下降，PDK1 过表达可挽救 细胞中的凋亡。PDK1 和 AKT 抑制剂联合在 中引起凋亡，但作为单一药物作用不大。
我们的研究结果表明， 预测对 PI3K/mTOR 抑制剂的反应，这可能导致针对 HNSCC 的首个基于生物标志物的靶向治疗，并且靶向 PDK1 可使 对 PI3K/mTOR 通路抑制剂敏感。
