Eli Lilly and Company, Lilly Research Laboratories, Oncology Discovery Research, Indianapolis, IN, USA.
Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Sci Rep. 2019 Oct 25;9(1):15365. doi: 10.1038/s41598-019-51981-5.
Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4-RET and LMNA-NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
抗 EGFR 抗体在晚期结直肠癌（CRC）的治疗中有效；然而，许多肿瘤无反应或产生耐药性。我们对接受西妥昔单抗（一种 EGFR 抑制剂）治疗的 25 例 CRC 患者前瞻性收集的肿瘤样本进行了内在和获得性耐药的基因组分析。在 25 例 CRC 患者中，有 13 例对西妥昔单抗表现出内在耐药性；12 例为内在敏感。我们从内在敏感患者中获得了 6 个获得性耐药时的再活检样本。在内在耐药患者中发现了 NCOA4-RET 和 LMNA-NTRK1 融合以及 NRG1 和 GNAS 扩增。在西妥昔单抗敏感患者中，我们发现了 KRAS K117N 和 A146T 突变，此外还有 BRAF V600E、AKT1 E17K、PIK3CA E542K 和 FGFR1 或 ERBB2 扩增。基线肿瘤与获得性耐药肿瘤的比较显示，体细胞变异的变异等位基因频率发生了极端变化，这表明西妥昔单抗暴露极大地选择了最初无法检测到的罕见耐药亚克隆。获得性耐药时还发生了上皮-间充质转化的增加，免疫浸润减少。此外，对获得性耐药的患者来源细胞系的特征分析表明，PI3K/mTOR 抑制可以挽救西妥昔单抗的耐药性。因此，我们发现了新的基因组改变，阐明了转移性 CRC 患者对抗 EGFR 治疗的敏感性和耐药性的机制。
