Integrated Biology of Rare Tumors, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
Department of Mental Health and Public Medicine, Section of Statistics, Università Degli Studi Della Campania Luigi Vanvitelli, 80138, Naples, Italy.
J Exp Clin Cancer Res. 2023 Apr 11;42(1):83. doi: 10.1186/s13046-023-02651-y.
Validated prognostic biomarkers for anti-angiogenic therapy using the anti-VEGF antibody Bevacizumab in ovarian cancer (OC) patients are still an unmet clinical need. The EGFR can contribute to cancer-associated biological mechanisms in OC cells including angiogenesis, but its targeting gave disappointing results with less than 10% of OC patients treated with anti-EGFR compounds showing a positive response, likely due to a non adequate selection and stratification of EGFR-expressing OC patients.
EGFR membrane expression was evaluated by immunohistochemistry in a cohort of 310 OC patients from the MITO-16A/MANGO-OV2A trial, designed to identify prognostic biomarkers of survival in patients treated with first line standard chemotherapy plus bevacizumab. Statistical analyses assessed the association between EGFR and clinical prognostic factors and survival outcomes. A single sample Gene Set Enrichment-like and Ingenuity Pathway Analyses were applied to the gene expression profile of 195 OC samples from the same cohort. In an OC in vitro model, biological experiments were performed to assess specific EGFR activation.
Based on EGFR-membrane expression, three OC subgroups of patients were identified being the subgroup with strong and homogeneous EGFR membrane localization, indicative of possible EGFR out/in signalling activation, an independent negative prognostic factor for overall survival of patients treated with an anti-angiogenic agent. This OC subgroup resulted statistically enriched of tumors of histotypes different than high grade serous lacking angiogenic molecular characteristics. At molecular level, among the EGFR-related molecular traits identified to be activated only in this patients' subgroup the crosstalk between EGFR with other RTKs also emerged. In vitro, we also showed a functional cross-talk between EGFR and AXL RTK; upon AXL silencing, the cells resulted more sensitive to EGFR targeting with erlotinib.
Strong and homogeneous cell membrane localization of EGFR, associated with specific transcriptional traits, can be considered a prognostic biomarker in OC patients and could be useful for a better OC patients' stratification and the identification of alternative therapeutic target/s in a personalized therapeutic approach.
在卵巢癌（OC）患者中使用抗血管内皮生长因子（VEGF）抗体贝伐珠单抗进行抗血管生成治疗，仍然存在未满足的临床需求。表皮生长因子受体（EGFR）可促进 OC 细胞中的癌症相关生物学机制，包括血管生成，但针对 EGFR 的治疗结果令人失望，接受抗 EGFR 化合物治疗的 OC 患者中不到 10%表现出阳性反应，这可能是由于对 EGFR 表达的 OC 患者的选择和分层不足。
在 MITO-16A/MANGO-OV2A 试验的 310 名 OC 患者队列中，通过免疫组织化学评估 EGFR 膜表达。该试验旨在确定接受一线标准化疗加贝伐珠单抗治疗的患者的生存预后生物标志物。统计分析评估了 EGFR 与临床预后因素和生存结果之间的关联。对来自同一队列的 195 名 OC 样本的基因表达谱进行了单个样本基因集富集分析和 Ingenuity 通路分析。在 OC 的体外模型中，进行了生物学实验来评估特定的 EGFR 激活。
基于 EGFR 膜表达，确定了 3 个 OC 患者亚组，其中 EGFR 膜定位强且均匀的亚组，提示可能存在 EGFR 内外信号激活，这是接受抗血管生成药物治疗的患者总生存的独立负预后因素。该 OC 亚组在统计学上富集了组织学类型不同于高级别浆液性且缺乏血管生成分子特征的肿瘤。在分子水平上，在所确定的仅在该患者亚组中激活的 EGFR 相关分子特征中，EGFR 与其他 RTKs 之间的串扰也出现了。在体外，我们还显示 EGFR 和 AXL RTK 之间存在功能串扰；在 AXL 沉默后，细胞对 EGFR 靶向药物厄洛替尼更敏感。
EGFR 细胞膜的强和均匀定位，与特定的转录特征相关，可作为 OC 患者的预后生物标志物，有助于更好地对 OC 患者进行分层，并在个体化治疗方法中确定替代治疗靶点。
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