肿瘤细胞治疗研究
英文原题：EGFR R521K Polymorphism Is Not a Major Determinant of Clinical Cetuximab Resistance in Head and Neck Cancer.
我们的结果提示，与此前报道不同，EGFR R521K 无法在 HNSCC 患者中引起西妥昔单抗耐药；因此，在治疗选择前对其进行筛查并不合理。
背景：头颈部鳞状细胞癌（HNSCC）是全球最常见的恶性肿瘤之一。复发/转移性患者接受含西妥昔单抗的联合化疗；西妥昔单抗是靶向表皮生长因子受体（EGFR）的单克隆抗体，可增强化疗作用，但相当一部分患者仍会产生治疗耐药。耐药机制尚未明确；已有研究报告 EGFR 胞外结构改变，并提出其可能导致西妥昔单抗治疗失败。 目的：本研究考察多外显子缺失变体 EGFRvIII 和单核苷酸多态性 EGFR R521K 对西妥昔单抗疗效的潜在影响。 结果：HNSCC 患者中 EGFRvIII 等位基因频率低于 1%，因此不太可能造成普遍耐药。EGFR R521K 存在于 42% 的患者中；研究者在 4 种 HNSCC 细胞系（2 种野生型、2 种 EGFR R521K 杂合型）中进行了研究。虽然未发现与 EGFR 状态直接相关的效应，但在 ADCC 试验和体内异种移植试验中，携带 R521K 的细胞敏感性较低。然而，这种临床前差异并未反映在 HNSCC 患者的无进展生存期或总生存期上。此外，肿瘤中的 NK 细胞和巨噬细胞数量与 EGFR R521K 无关。 讨论：结果提示，与既往报道不同，EGFR R521K 不会导致 HNSCC 患者对西妥昔单抗耐药，因此不应以治疗选择为目的在治疗前筛查该变异。
BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are among the most abundant malignancies worldwide. Patients with recurrent/metastatic disease undergo combination chemotherapy containing cetuximab, the monoclonal antibody used against the epidermal growth factor receptor (EGFR). Cetuximab augments the effect of chemotherapy; however, a significant number of patients show therapy resistance. The mechanism of resistance is yet to be unveiled, although extracellular alterations of the receptor have been reported, and their role in cetuximab failure has been proposed. AIMS: Here, we investigate possible effects of the multi-exon deletion variant (EGFRvIII), and the single nucleotide polymorphism EGFR R521K on cetuximab efficacy. RESULTS: Our results show that in HNSCC patients, the EGFRvIII allele frequency is under 1%; therefore, it cannot lead to common resistance. EGFR R521K, present in 42% of the patients, is investigated in vitro in four HNSCC cell lines (two wild-type and two heterozygous for EGFR R521K). While no direct effect is found to be related to the EGFR status, cells harboring R521K show a reduced sensitivity in ADCC experiments and in vivo xenograft experiments. However, this preclinical difference is not reflected in the progression-free or overall survival of HNSCC patients. Furthermore, NK cell and macrophage presence in tumors is not related to EGFR R521K. DISCUSSION: Our results suggest that EGFR R521K, unlike reported previously, is unable to cause cetuximab resistance in HNSCC patients; therefore, its screening before therapy selection is not justifiable.
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