表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）的临床疗效受药物耐药性的限制。我们假设在EGFR-TKIs初次治疗下恢复失调的环状RNA可能增强它们的有效性。通过高通量筛选，我们鉴定出将环状RNA IGF1R（cIGF1R）与EGFR-TKIs结合显著协同抑制药物停用后的肿瘤再生长。机制上，cIGF1R与RNA解旋酶A（RHA）相互作用，抑制胰岛素样生长因子1受体（IGF1R）的mRNA剪接，负向调控IGF1R信号通路的母本。这种调控与IGF1R抑制剂相似，后者诱导具有活跃线粒体自噬的耐药持续状态。cIGF1R还编码一种C-IGF1R肽，能够减少Parkin介导的电压依赖性阴离子通道1（VDAC1）的泛素化，限制线粒体自噬，作为促进耐药持续状态向凋亡转变的分子开关。我们的研究表明，将cIGF1R与EGFR-TKIs结合能够有效减少耐药持续状态的产生。© 2023. 作者，ADMCAssociazione Differenziamento e Morte Cellulare独家许可。

The clinical efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) is limited by the emergence of drug resistance. We hypothesise that restoring dysregulated circular RNAs under initial treatment with EGFR-TKIs may enhance their effectiveness. Through high-throughput screening, we identify that combining circular RNA IGF1R (cIGF1R) with EGFR-TKIs significantly synergises to suppress tumour regrowth following drug withdrawal. Mechanistically, cIGF1R interacts with RNA helicase A (RHA) to depress insulin-like growth factor 1 receptor (IGF1R) mRNA splicing, negatively regulating the parent IGF1R signalling pathway. This regulation is similar to that of IGF1R inhibitor, which induces drug-tolerant persister (DTP) state with activated mitophagy. The cIGF1R also encodes a peptide C-IGF1R that reduces Parkin-mediated ubiquitination of voltage-dependent anion channel 1 (VDAC1) to restrict mitophagy, acting as a molecular switch that promotes the transition of DTP to apoptosis. Our study shows that combining cIGF1R with EGFR-TKIs efficiently reduces the emergence of DTP.© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.