Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, PR China.
Clinical Trial Center, The Affiliated Hospital of Qingdao University, Qingdao 266003, PR China.
Pharmacol Res. 2021 Dec;174:105934. doi: 10.1016/j.phrs.2021.105934. Epub 2021 Oct 11.
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.
小细胞肺癌 (SCLC) 的耐药性显著影响化疗治疗的疗效。然而，由于肿瘤组织样本缺乏，特别是化疗期间的连续肿瘤样本，化疗耐药的机制尚未得到充分研究。循环肿瘤 DNA 可以非侵入性地获得，它可以补充肿瘤采样方法，用于该领域的研究。我们从 52 名可获得随访数据的 SCLC 患者中鉴定出一名获得性耐药患者。通过比较化疗前后循环肿瘤 DNA 中的体细胞突变，我们首次发现 eIF3A R803K 体细胞突变可能与获得性化疗耐药有关。然后，通过接受化疗的 254 名肺癌患者的样本证实了 eIF3A R803K 突变与化疗耐药之间的关联。我们发现 eIF3a R803K 突变削弱了肿瘤细胞的增殖能力，但增加了它们对化疗的耐药性。进一步的研究表明，eIF3A R803K 突变促进细胞衰老。此外，非瑟酮在 eIF3A R803K 突变细胞中与化疗具有协同作用。这些结果表明，eIF3A R803K 体细胞突变有可能预测 SCLC 的化疗耐药性。此外，eIF3A R803K 突变通过诱导衰老促进化疗耐药性。此外，一种衰老细胞溶解药物非瑟酮可以逆转由 eIF3A R803K 突变介导的化疗耐药性。
