Moores Cancer Center, University of California, San Diego, La Jolla, California.
Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Mol Cancer Ther. 2020 Jul;19(7):1562-1571. doi: 10.1158/1535-7163.MCT-19-1036. Epub 2020 May 19.
Cetuximab, an mAb targeting EGFR, is a standard of care for the treatment for locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC). However, despite overexpression of EGFR in more than 90% of HNSCC lesions, most patients with HNSCC fail to respond to cetuximab treatment. In addition, there are no available biomarkers to predict sensitivity or resistance to cetuximab in the clinic. Here, we sought to advance precision medicine approaches for HNSCC by identifying PI3K/mTOR signaling network-specific cetuximab resistance mechanisms. We first analyzed the frequency of genomic alterations in genes involved in the PI3K/mTOR signaling circuitry in the HNSCC TCGA dataset. Experimentally, we took advantage of CRISPR/Cas9 genome editing approaches to systematically explore the contribution of genomic alterations in each tumor suppressor gene (TSG) controlling the PI3K-mTOR pathway to cetuximab resistance in HNSCC cases that do not exhibit mutations. Remarkably, we found that many HNSCC cases exhibit pathway-specific gene copy number loss of multiple TSGs that normally restrain PI3K/mTOR signaling. Among them, we found that both engineered and endogenous gene deletions can mediate resistance to cetuximab. Our findings suggest that gene copy number loss, which is highly prevalent in HNSCC, may result in sustained PI3K/mTOR signaling independent of EGFR, thereby representing a promising mechanistic biomarker predictive of cetuximab resistance in this cancer type. Further prospective studies are needed to investigate the impact of loss on cetuximab efficacy in the clinic.
西妥昔单抗（一种针对 EGFR 的 mAb）是治疗局部晚期或转移性头颈部鳞状细胞癌（HNSCC）的标准治疗方法。然而，尽管超过 90%的 HNSCC 病变中 EGFR 过度表达，但大多数 HNSCC 患者对西妥昔单抗治疗无反应。此外，临床上没有可用的生物标志物来预测对西妥昔单抗的敏感性或耐药性。在这里，我们通过鉴定 PI3K/mTOR 信号网络特异性西妥昔单抗耐药机制，旨在推进 HNSCC 的精准医学方法。我们首先分析了 HNSCC TCGA 数据集中涉及 PI3K/mTOR 信号通路的基因的基因组改变频率。在实验中，我们利用 CRISPR/Cas9 基因组编辑方法系统地探索了控制 PI3K-mTOR 通路的每个肿瘤抑制基因（TSG）中的基因组改变对不显示突变的 HNSCC 病例中对西妥昔单抗耐药的贡献。值得注意的是，我们发现许多 HNSCC 病例表现出多种 TSG 的通路特异性基因拷贝数丢失，这些 TSG 通常抑制 PI3K/mTOR 信号。其中，我们发现工程和内源性基因缺失都可以介导对西妥昔单抗的耐药性。我们的研究结果表明，在 HNSCC 中高度普遍存在的基因拷贝数丢失可能导致 PI3K/mTOR 信号的持续激活，而不依赖于 EGFR，从而代表了一种有前途的机制生物标志物，可预测这种癌症类型对西妥昔单抗的耐药性。需要进一步的前瞻性研究来研究在临床上基因缺失对西妥昔单抗疗效的影响。
