EGFR 突变的非小细胞肺癌 (NSCLC) 患者受益于针对 EGFR 的酪氨酸激酶抑制剂 (TKI) 治疗。尽管患者护理有所改善，特别是使用第三代 TKI 奥希替尼，但所有患者均观察到疾病复发。在涉及 TKI 耐药的各种过程中，上皮间质转化 (EMT) 尚未得到充分表征。我们假设细胞朊病毒蛋白 PrPC 可能参与 NSCLC 的 EMT 和 EGFR-TKI 耐药。使用 5 个独立的肺腺癌数据集（包括我们自己的队列），我们记录了编码 PrPC 的 PRNP 基因的表达与 EMT 相关。通过操纵不同 EGFR 突变 NSCLC 细胞系中 PrPC 的水平，我们确信 PrPC 的表达对于细胞维持或获得间充质表型是必需的。从机制上讲，我们表明 PrPC 通过 ILK-RBPJ 级联起作用，该级联还控制 EGFR 的表达。我们的数据进一步证明，与野生型肿瘤相比，EGFR 突变肿瘤中或体外 EGFR 激活后，PrPC 水平升高。此外，我们提供的证据表明 PRNP 水平随着 TKI 耐药而增加，并且减少 PRNP 表达会使细胞对奥希替尼敏感。最后，我们发现来自 2 个独立队列的 EGFR 突变 NSCLC 患者血浆 PrPC 水平升高，并且它们的纵向演变反映了疾病的纵向演变。总而言之，这些发现将 PrPC 定义为 NSCLC 中 EMT 依赖性 EGFR-TKI 耐药的候选驱动因素。他们进一步表明，监测血浆 PrPC 水平可能代表一种有价值的患者随访非侵入性策略，并值得考虑对 TKI 失败的 EGFR 突变 NSCLC 患者进行 PrPC 靶向治疗。© 2024。作者。

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) benefit from treatment with tyrosine kinase inhibitors (TKI) targeting EGFR. Despite improvements in patient care, especially with the 3rd generation TKI osimertinib, disease relapse is observed in all patients. Among the various processes involved in TKI resistance, epithelial-to-mesenchymal transition (EMT) is far from being fully characterized. We hypothesized that the cellular prion protein PrPC could be involved in EMT and EGFR-TKI resistance in NSCLC. Using 5 independent lung adenocarcinoma datasets, including our own cohort, we document that the expression of the PRNP gene encoding PrPC is associated with EMT. By manipulating the levels of PrPC in different EGFR-mutated NSCLC cell lines, we firmly establish that the expression of PrPC is mandatory for cells to maintain or acquire a mesenchymal phenotype. Mechanistically, we show that PrPC operates through an ILK-RBPJ cascade, which also controls the expression of EGFR. Our data further demonstrate that PrPC levels are elevated in EGFR-mutated versus wild-type tumours or upon EGFR activation in vitro. In addition, we provide evidence that PRNP levels increase with TKI resistance and that reducing PRNP expression sensitizes cells to osimertinib. Finally, we found that plasma PrPC levels are increased in EGFR-mutated NSCLC patients from 2 independent cohorts and that their longitudinal evolution mirrors that of disease. Altogether, these findings define PrPC as a candidate driver of EMT-dependent resistance to EGFR-TKI in NSCLC. They further suggest that monitoring plasma PrPC levels may represent a valuable non-invasive strategy for patient follow-up and warrant considering PrPC-targeted therapies for EGFR-mutated NSCLC patients with TKI failure.© 2024. The Author(s).