Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medicine, Chicago, IL, USA.
Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi, India.
Cancer Gene Ther. 2024 Oct;31(10):1477-1485. doi: 10.1038/s41417-024-00812-5. Epub 2024 Jul 31.
Cetuximab induces responses in about 13% of head and neck squamous cell carcinomas (HNSCC). We describe the molecular mechanism of acquired resistance to cetuximab, which could be overcome by switching to a different anti-EGFR antibody. Biopsies were collected at three different time points: before the start of cetuximab (PRE-cetux), at acquired resistance to cetuximab (AR-cetux), and at acquired resistance to duligotuzumab (AR-duligo). Biopsies were analyzed using tumor and normal whole-exome sequencing, RNASeq, and targeted panel sequencing with ultra-deep coverage to generate differential mutation and expression profiles. WES and targeted sequencing analysis identified an EGFR p.G465R extracellular domain mutation in AR-cetux biopsy. Furthermore, RNASeq confirmed the expression of this mutation in the tumor tissue. This mutation prevented the binding of cetuximab to EGFR and was not present in PRE-cetux and AR-duligo biopsies, suggesting a potential mechanism of acquired resistance to cetuximab. Molecular dynamic simulations confirmed that duligotuzumab effectively binds EGFR with a p.G465R mutation. Interestingly, the p.G465R mutation improved the stability of the duligotuzumab-EGFR complex as compared to the wild-type EGFR. This is the first report of an EGFR ECD mutation associated with acquired resistance to cetuximab, posing a need for further validation. We suggest appropriate serial mutational profiling to identify ECD mutations should be considered for select patients with initial cetuximab benefit.
西妥昔单抗可诱导约 13%的头颈部鳞状细胞癌（HNSCC）产生应答。我们描述了获得性对西妥昔单抗耐药的分子机制，通过切换到另一种抗 EGFR 抗体可以克服这种耐药性。在三个不同的时间点采集活检：在开始西妥昔单抗治疗之前（PRE-cetux）、获得性对西妥昔单抗耐药时（AR-cetux）和获得性对杜利妥珠单抗耐药时（AR-duligo）。使用肿瘤和正常全外显子测序、RNAseq 和靶向panel 测序进行活检分析，具有超深度覆盖，以生成差异突变和表达谱。WES 和靶向测序分析在 AR-cetux 活检中鉴定出 EGFR p.G465R 细胞外结构域突变。此外，RNAseq 证实了该突变在肿瘤组织中的表达。该突变阻止了西妥昔单抗与 EGFR 的结合，并且在 PRE-cetux 和 AR-duligo 活检中均不存在，提示了获得性对西妥昔单抗耐药的潜在机制。分子动力学模拟证实，杜利妥珠单抗可有效结合具有 p.G465R 突变的 EGFR。有趣的是，与野生型 EGFR 相比，p.G465R 突变提高了杜利妥珠单抗-EGFR 复合物的稳定性。这是首例与获得性对西妥昔单抗耐药相关的 EGFR ECD 突变的报道，需要进一步验证。我们建议，对于初始西妥昔单抗获益的部分患者，应考虑进行适当的连续突变分析，以识别 ECD 突变。
