eIF3a R803K mutation mediates chemotherapy resistance by inducing cellular senescence in small cell lung cancer

Release time:2023-02-02

Impact Factor:10.334

DOI number:10.1016/j.phrs.2021.105934

Affiliation of Author(s):Xiangya Hospital, Central South University

Teaching and Research Group:Department of Clinical Pharmacology

Journal:Pharmacological research

Place of Publication:Netherlands

Funded by:国家自然科学基因项目

Key Words:Cellular senescence; Chemotherapy resistance; Circulating tumor DNA; Cisplatin (PubChem CID: 5702198); Cycloheximide (PubChem CID: 6197); EIF3a mutation; Etoposide (PubChem CID: 36462); Fisetin (PubChem CID: 5281614); MG132 (PubChem CID: 462382); SCR7 (PubChem CID: 10688007); Small cell lung cancer

Abstract:Drug resistance in small cell lung cancer (SCLC) significantly affects the efficacy of chemotherapy treatment. However, due to the lack of tumor tissue samples, especially serial tumor samples during chemotherapy, the mechanism of chemotherapy resistance has not been fully studied. Circulating tumor DNA, which can be obtained in a noninvasive manner, can complement tumor sampling approaches for research in this field. We identified an SCLC patient with acquired drug resistance from 52 SCLC patients for whom follow-up data were available. By comparing somatic mutations in circulating tumor DNA before and after chemotherapy, for the first time, we found that the somatic mutation eIF3A R803K may be related to acquired chemotherapy resistance. Then, the association between the eIF3A R803K mutation and chemotherapy resistance was confirmed by samples from 254 lung cancer patients receiving chemotherapy. We found that the eIF3a R803K mutation weakened the proliferation ability of tumor cells but increased their resistance to chemotherapy. Further studies revealed that the eIF3A R803K mutation promotes cellular senescence. In addition, fisetin showed a synergistic effect with chemotherapy in eIF3A R803K mutant cells. These results suggest that the eIF3A R803K somatic mutation has the potential to predict chemotherapy resistance in SCLC. Moreover, the eIF3A R803K mutation promotes chemotherapy resistance by inducing senescence. Furthermore, a senolytic drug, fisetin, can reverse chemotherapy resistance mediated by the eIF3A R803K mutation

Co-author:Chen-Jing Wang, De-Sheng Xiao, Bai-Mei He, Min Li, Xiao-Ping Yi, Wei Zhang

First Author:Yi-Xin Chen

Indexed by:Article

Correspondence Author:Ji-Ye Yin, Zhao-Qian Liu

Discipline:Medicine

First-Level Discipline:Pharmaceutical Science

Document Type:J

Volume:174

Page Number:105934

ISSN No.:1043-6618

Translation or Not:no

Date of Publication:2021-10-11

Included Journals:SCI

Links to published journals:https://www.sciencedirect.com/science/article/abs/pii/S1043661821005181?via%3Dihub