<br>靶向 GSTP1 作为肺腺癌干性和酪氨酸激酶抑制剂耐药性的治疗策略,Advanced Science

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靶向 GSTP1 作为肺腺癌干性和酪氨酸激酶抑制剂耐药性的治疗策略
Advanced Science ( IF 14.3 ) Pub Date : 2023-01-29 , DOI: 10.1002/advs.202205262
Si-Qi Wang _{1,

2,

3,

4} , Jun-Jiang Chen _{5,

6} , Yuchen Jiang ₇ , Zi-Ning Lei ₇ , Ye Chun Ruan ₆ , Yihang Pan ₇ , Judy Wai Ping Yam ₂ , Maria Pik Wong ₂ , Zhi-Jie Xiao ₇

Affiliation

谷胱甘肽 S-转移酶pi (GSTP1) 是一种 II 期解毒酶，已知其过度表达并介导肺癌化疗耐药。然而，GSTP1 是否支持癌症干细胞 (CSC) 以及肺腺癌 (LUAD) 的潜在机制仍然很大程度上未知。这项研究揭示了 GSTP1 在肺 CSC 中上调，并在体外和体内支持肿瘤的自我更新、转移和对 LUAD 靶向酪氨酸激酶抑制剂的耐药性。从机制上讲，CaMK2A（钙/钙调蛋白依赖性蛋白激酶 2 亚型 A）/NRF2（核因子红细胞 2 相关因子 2）/GSTP1 被发现是缺氧下的调节轴。 CaMK2A 通过磷酸化 NRF2 的 Sersine558 残基并促进其核转位来增加 GSTP1 表达，这是一种不同于传统氧化依赖性激活的新 NRF2 激活机制。 GSTP1 的上调反过来又抑制活性氧水平并支持 CSC 表型。临床上，通过免疫组织化学分析，GSTP1 在部分 LUAD 中上调，可作为生存的预后标志物。使用来自ALK转位 LUAD 的患者来源的类器官，证明了特定 GSTP1 抑制剂 ezatiostat 与 ALK 抑制剂克唑替尼联合治疗的治疗潜力。这项研究表明 GSTP1 是通过靶向 CSC 长期控制 LUAD 的有前途的治疗靶点。

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Targeting GSTP1 as Therapeutic Strategy against Lung Adenocarcinoma Stemness and Resistance to Tyrosine Kinase Inhibitors

Glutathione S-transferase pi (GSTP1), a phase II detoxification enzyme, is known to be overexpressed and mediates chemotherapeutic resistance in lung cancer. However, whether GSTP1 supports cancer stem cells (CSCs) and the underlying mechanisms in lung adenocarcinoma (LUAD) remain largely unknown. This study unveiled that GSTP1 is upregulated in lung CSCs and supports tumor self-renewal, metastasis, and resistance to targeted tyrosine kinase inhibitors of LUAD both in vitro and in vivo. Mechanistically, CaMK2A (calcium/calmodulin-dependent protein kinase 2 isoform A)/NRF2 (nuclear factor erythroid 2-related factor 2)/GSTP1 is uncovered as a regulatory axis under hypoxia. CaMK2A increased GSTP1 expression through phosphorylating the Sersine558 residue of NRF2 and promoting its nuclear translocation, a novel mechanism for NRF2 activation apart from conventional oxidization-dependent activation. Upregulation of GSTP1 in turn suppressed reactive oxygen species levels and supported CSC phenotypes. Clinically, GSTP1 analyzed by immunohistochemistry is upregulated in a proportion of LUAD and serves as a prognostic marker for survival. Using patient-derived organoids from an ALK-translocated LUAD, the therapeutic potential of a specific GSTP1 inhibitor ezatiostat in combination treatment with the ALK inhibitor crizotinib is demonstrated. This study demonstrates GSTP1 to be a promising therapeutic target for long-term control of LUAD through targeting CSCs.

更新日期：2023-01-29

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