Despite the success of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations, intrinsic or acquired resistance remains the major obstacle to long-term disease remission. Defective autophagy has been reported as an EGFR-TKI resistance mechanism. However, how EGFR regulate autophagic flux are still not fully understood. Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturbs the sequestration function of SQSTM1 and causes autophagic flux blocking. SAH-EJ2, a staple optimized EGFR-derived peptide, showed enhanced in vitro and in vivo antitumor activity against NSCLC than the prototype regardless of EGFR mutation status. Mechanistically, SAH-EJ2 disrupts the EGFR-SQSTM1 interaction and protects against EGFR-induced SQSTM1 phosphorylation, which hinders the dimerization of the SQSTM1 UBA domains and restores SQSTM1 cargo function. Moreover, SAH-EJ2 suppresses EGFR activity by blocking its dimerization and reducing its protein stability, which reciprocally activates the core autophagy machinery. Our observations reveal that disturbing the EGFR-SQSTM1 interaction by SAH-EJ2 confers a potential strategy in the treatment of NSCLC through suppressing EGFR signalling and activating autophagy simultaneously.

中文翻译：

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固定肽破坏EGFR-SQSTM1相互作用可通过激活自噬和抑制EGFR信号传导来抑制肺癌。

尽管表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）在具有EGFR激活突变的非小细胞肺癌（NSCLC）的治疗中取得了成功，但内在或获得性耐药仍然是长期疾病缓解的主要障碍。自噬缺陷被报道为EGFR-TKI耐药机制。但是，EGFR如何调节自噬通量仍未完全了解。在这里，我们发现在酪氨酸433处EGFR刺激的SQSTM1磷酸化诱导了其UBA结构域的二聚化，这干扰了SQSTM1的螯合功能并引起自噬通量阻断。SAH-EJ2是一种最优化的EGFR衍生肽，无论其突变状态如何，其对NSCLC的体外和体内抗肿瘤活性均高于原型。机械上，SAH-EJ2破坏了EGFR-SQSTM1的相互作用，并防止EGFR诱导的SQSTM1磷酸化，这阻碍了SQSTM1 UBA结构域的二聚化并恢复了SQSTM1的货物功能。此外，SAH-EJ2通过阻止其二聚化并降低其蛋白质稳定性来抑制EGFR活性，从而相互激活了核心自噬机制。我们的观察结果表明，通过SAH-EJ2干扰EGFR-SQSTM1相互作用可通过抑制EGFR信号传导并同时激活自噬而赋予NSCLC潜在的治疗策略。相互激活核心自噬机制。我们的观察结果表明，通过抑制EGFR信号传导并同时激活自噬，通过SAH-EJ2干扰EGFR-SQSTM1相互作用赋予了治疗NSCLC的潜在策略。相互激活核心自噬机制。我们的观察结果表明，通过抑制EGFR信号传导并同时激活自噬，通过SAH-EJ2干扰EGFR-SQSTM1相互作用赋予了治疗NSCLC的潜在策略。