Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) greatly improved clinical outcomes of patients with non-small cell lung cancer (NSCLC). Unfortunately, primary and acquired resistance limits their clinical benefits. To overcome such resistance, new generations of EGFR TKIs have been developed by targeting newly identified mutations in EGFR. However, much less effort has been put into alternative strategies, such as targeting the intrinsic protective responses to EGFR TKIs. In this study, we found that EGFR TKIs, including gefitinib and AZD9291, impaired lysosome-dependent degradation of SQSTM1, thus compromising their anti-cancer efficiency. By accumulating in the lysosome lumen, gefitinib and AZD9291 attenuated lysosomal acidification and impaired autolysosomal degradation of SQSTM1 owing to their intrinsic alkalinity. As a result, SQSTM1 protein was stabilized in response to gefitinib and AZD9291 treatment and conferred EGFR TKI resistance. Depleting SQSTM1 significantly increased the sensitivity of NSCLC cells to gefitinib and AZD9291 both in vitro and in vivo. Furthermore, a chemically modified gefitinib analog lacking alkalinity displayed stronger inhibitory effects on NSCLC cells. Therefore, targeting accumulated SQSTM1 or chemically modified EGFR TKIs may represent new strategies to increase the effectiveness of EGFR targeted therapy.

表皮生长因子受体（EGFR TKI）的酪氨酸激酶抑制剂极大地改善了非小细胞肺癌（NSCLC）患者的临床结果。不幸的是，原发性和获得性耐药性限制了它们的临床益处。为了克服这种耐药性，通过针对新发现的 EGFR 突变，开发了新一代 EGFR TKI。然而，在替代策略上投入的精力要少得多，例如针对 EGFR TKI 的内在保护反应。在这项研究中，我们发现 EGFR TKI，包括吉非替尼和 AZD9291，会损害 SQSTM1 的溶酶体依赖性降解，从而损害其抗癌效率。通过在溶酶体腔中积聚，吉非替尼和 AZD9291 由于其固有的碱性而减弱了溶酶体酸化并损害了 SQSTM1 的自溶酶体降解。结果，SQSTM1 蛋白对吉非替尼和 AZD9291 治疗的反应稳定，并赋予 EGFR TKI 耐药性。耗尽 SQSTM1 可以显着增加 NSCLC 细胞在体外和体内对吉非替尼和 AZD9291 的敏感性。此外，缺乏碱性的化学修饰的吉非替尼类似物对NSCLC细胞表现出更强的抑制作用。因此，靶向积累的SQSTM1或化学修饰的EGFR TKI可能代表提高EGFR靶向治疗有效性的新策略。