Arsenic circumvents the gefitinib resistance by binding to P62 and mediating autophagic degradation of EGFR in non-small cell lung cancer

作者：Mao, Jianhua; Ma, Lie; Shen, Yan; Zhu, Kongkai; Zhang, Ru; Xi, Wenda; Ruan, Zheng; Luo, Cheng; Chen, Zhu; Xi, Xiaodong^*; Chen, Saijuan^*

来源：Cell Death & Disease, 2018, 9(10): 963.

DOI：10.1038/s41419-018-0998-7

• INHIBITOR
• MUTATIONS
• MECHANISMS
• PML/RARA
• MUTANT
• AZD9291
• TRIAL
• FORM

Non-small cell lung cancer (NSCLC) is characterized by hyperexpression and/or gain-of-function mutations of the epidermal growth factor receptor (EGFR), resulting in an elevated overall kinase activity. Gefitinib is remarkably effective in patients with the L858R or AE746-A750-mutated of EGFR. However, drug resistance tends to develop because of the emergence of T790M mutation on EGFR. New strategies other than repressing kinase activity are thus required to treat NSCLC, thereby circumventing the resistance. In this study, arsenic trioxide (ATO) at 2 pM significantly inhibited the proliferation of the gefitinib-resistant NCI-H1975 cells of the EGFR L8581V1 790M mutant compared with a modest inhibition in the gefitinib-sensitive HCC827 cells of AE746-A750 mutant and A549 cells of wild-type EGFR. Moreover, ATO significantly inhibited the overall kinase activity of EGFR primarily through quantitatively diminishing the EGFR in NCI-H1975 cells to an extent comparable with that reached by gefitinib in HCC827 cells. Furthermore, ATO promoted autophagic degradation of EGFR in NSCLC cells by directly binding to P62, which interacted with EGFR, preferentially the L8581V1 790M mutant providing a plausible explanation for a more favorable effect of ATO on NOH1975 cells. Accordingly, the effect of ATO was further confirmed in the NSCLC xenograft mouse models. Our results reveal a new target for ATO with a unique molecular mechanism, i.e., ATO suppresses the overall catalytic potential of EGFR, significantly those with the L858R/T790M mutant in NCI-H1975 cells, through an autophagic degradation by interacting with P62. This study potentially offers an innovative therapeutic avenue for the NSCLC with L858R/T790-Mmutated EGFR.

• 出版日期2018-9-20
• 单位上海市闵行区中心医院; 新药研究国家重点实验室; 医学基因组学国家重点实验室; 中国科学院; 中国科学院上海药物研究所; 上海交通大学