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 PIK3CA 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 PTEN gene deletions can mediate resistance to cetuximab. Our findings suggest that PTEN 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 PTEN loss on cetuximab efficacy in the clinic.

中文翻译：

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PI3K/mTOR 肿瘤抑制基因的通路特异性基因组编辑揭示 PTEN 缺失导致头颈癌中的西妥昔单抗耐药


西妥昔单抗是一种靶向 EGFR 的单克隆抗体，是治疗局部晚期或转移性头颈鳞状细胞癌 (HNSCC) 的标准治疗方法。然而，尽管 90% 以上的 HNSCC 病变中 EGFR 过度表达，但大多数 HNSCC 患者对西妥昔单抗治疗没有反应。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，我们试图通过识别 PI3K/mTOR 信号网络特定的西妥昔单抗耐药机制来推进 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。在实验上，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) 的基因组改变对不表现出 PIK3CA 突变的 HNSCC 病例中西妥昔单抗耐药性的贡献。值得注意的是，我们发现许多 HNSCC 病例表现出多个 TSG 的通路特异性基因拷贝数丢失，这些 TSG 通常抑制 PI3K/mTOR 信号传导。其中，我们发现工程和内源性 PTEN 基因缺失均可介导西妥昔单抗耐药性。我们的研究结果表明，在 HNSCC 中非常普遍的 PTEN 基因拷贝数丢失可能导致独立于 EGFR 的持续 PI3K/mTOR 信号传导，从而代表了一种有前途的预测这种癌症类型中西妥昔单抗耐药性的机制生物标志物。需要进一步的前瞻性研究来调查 PTEN 缺失对西妥昔单抗临床疗效的影响。