PrPC控制表皮生长因子受体突变非小细胞肺癌中的上皮-间质转化：对酪氨酸激酶抑制剂耐药和患者随访的影响

PrPC controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up

ONCOGENE

影响因子:7.3

分区:医学1区 Top / 生化与分子生物学1区遗传学1区细胞生物学2区肿瘤学2区

发表日期:2024 Sep

作者: Claire Lailler, Audrey Didelot, Simon Garinet, Hugo Berthou, Marine Sroussi, Aurélien de Reyniès, Shoukat Dedhar, Séverine Martin-Lannerée, Elizabeth Fabre, Françoise Le Pimpec-Barthes, Alexandre Perrier, Virginie Poindessous, Audrey Mansuet-Lupo, Fatima Djouadi, Jean-Marie Launay, Pierre Laurent-Puig, Hélène Blons, Sophie Mouillet-Richard

DOI: 10.1038/s41388-024-03130-0

摘要

EGFR突变的非小细胞肺癌（NSCLC）患者通过靶向EGFR的酪氨酸激酶抑制剂（TKI）治疗获益。尽管患者护理有所改善，特别是第三代TKI奥希替尼，但所有患者都观察到疾病复发。在涉及TKI耐药的多种过程之中，上皮-间质转化（EMT）尚未完全阐明。我们假设细胞朊蛋白PrPC可能参与EMT以及EGFR-TKI耐药的机制。利用包括我们自己队列在内的五个独立肺腺癌数据集，我们发现编码PrPC的PRNP基因表达与EMT相关。通过操控不同EGFR突变NSCLC细胞系中的PrPC水平，我们明确表明PrPC的表达对于细胞维持或获得间质表型是必需的。机制上，我们显示PrPC通过ILK-RBPJ级联途径发挥作用，该通路同时调控EGFR的表达。我们的数据还表明，PrPC水平在EGFR突变肿瘤中高于野生型肿瘤，或在体外激活EGFR时升高。此外，PRNP水平随着TKI耐药而增加，降低PRNP表达可增强细胞对奥希替尼的敏感性。最后，我们发现EGFR突变的NSCLC患者中，血浆PrPC水平在两个独立队列中升高，其长期变化与疾病进展同步。综上所述，PrPC被定义为驱动NSCLC中EMT依赖性耐药的潜在因子，监测血浆PrPC水平或许是一种有价值的非侵入性患者随访策略，并建议考虑针对PrPC的治疗以应对EGFR突变NSCLC的TKI失败。

Abstract

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.