Acquired resistance to growth factor receptor tyrosine kinase inhibitors limits the therapeutic benefits gained by EGFR-mutant lung adenocarcinoma (LUAD) patients treated with gefitinib. Circular RNAs (circRNAs) are novel noncoding RNAs implicated in the regulation of chemoresistance in malignancies. However, whether circRNAs participate in the development of EGFR-TKI resistance in LUAD remains to be clarified. Here, we report that circASK1 (hsa_circ_0007798) is significantly downregulated in gefitinib-resistant cells and enhances the gefitinib sensitivity of LUAD cells. Mechanistically, we identified a novel protein encoded by circASK1, ASK1-272a.a, which is essential for ASK1/JNK/p38 signaling activation and mediates the chemosensitivity-inducing effect of circASK1 in LUAD. Importantly, this novel isoform competes with ASK1 for binding to Akt1, therefore antagonizing Akt1-induced ASK1 phosphorylation and inactivation, leading to the activation of ASK1-induced apoptosis and alleviating gefitinib resistance. Moreover, increased YTHDF2-mediated endoribonucleolytic cleavage of m⁶A-modified circASK1 accounts for its downregulation in gefitinib-resistant cells. The clinical data and in vivo model further corroborated the suppressive effect of circASK1 and its encoded protein on gefitinib resistance. Our study provides a novel therapeutic target to overcome gefitinib resistance in LUAD patients.

对生长因子受体酪氨酸激酶抑制剂的获得性耐药限制了使用吉非替尼治疗的 EGFR 突变肺腺癌 (LUAD) 患者获得的治疗益处。环状 RNA (circRNA) 是一种新型非编码 RNA，与恶性肿瘤化疗耐药性的调节有关。然而，circRNA是否参与了LUAD中EGFR-TKI耐药的发展仍有待阐明。在此，我们报告 circASK1 (hsa_circ_0007798) 在吉非替尼耐药细胞中显着下调，并增强 LUAD 细胞对吉非替尼的敏感性。从机制上讲，我们鉴定了一种由 circASK1 编码的新型蛋白 ASK1-272a.a，它对于 ASK1/JNK/p38 信号激活至关重要，并介导 circASK1 在 LUAD 中的化学敏感性诱导作用。重要的是，这种新型亚型与 ASK1 竞争与 Akt1 的结合，因此拮抗 Akt1 诱导的 ASK1 磷酸化和失活，从而激活 ASK1 诱导的细胞凋亡并减轻吉非替尼耐药。此外，YTHDF2介导的核糖核酸内切酶裂解增加⁶ A 修饰的 circASK1 是其在吉非替尼耐药细胞中下调的原因。临床数据和体内模型进一步证实了circASK1及其编码蛋白对吉非替尼耐药的抑制作用。我们的研究提供了一个新的治疗靶点来克服 LUAD 患者对吉非替尼的耐药性。