PRPC控制EGFR突变的NSCLC中的上皮到间质转变：对TKI耐药性和患者随访的影响
PrPC controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up
影响因子:7.30000
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
摘要
EGFR突变的非小细胞肺癌（NSCLC）的患者受益于靶向EGFR的酪氨酸激酶抑制剂（TKI）的治疗。尽管患者护理的改善，尤其是第三代TKI Osimertinib，但在所有患者中都观察到疾病复发。在TKI抗性涉及的各种过程中，上皮到间质转变（EMT）远非充分表征。我们假设细胞prion蛋白PRPC可能与NSCLC中的EMT和EGFR-TKI抗性有关。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氧化NSCLC细胞系中的PRPC水平，我们牢固地确定PRPC的表达必须使细胞维持或获取间充质表型。从机械上讲，我们表明PRPC通过ILK-RBPJ Cascade运行，该级联也控制EGFR的表达。我们的数据进一步表明，EGFR突变的野生型肿瘤或EGFR在体外激活后PRPC水平升高。此外，我们还提供了证据表明，PRNP水平随TKI耐药性而增加，并且降低PRNP表达会使细胞对osimertinib敏感。最后，我们发现来自2个独立队列的EGFR突变的NSCLC患者的血浆PRPC水平升高，并且它们的纵向进化反映了疾病的纵向进化。总之，这些发现将PRPC定义为NSCLC中对EGFR-TKI的EMT依赖性抗性的候选驱动力。他们进一步建议，监测血浆PRPC水平可能代表了患者随访的有价值的非侵入性策略，并考虑了针对EGFR突变的TKI衰竭患者的PRPC靶向疗法的保证。
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.