Minchom Anna, Thavasu Parames, Ahmad Zai, Stewart Adam, Georgiou Alexandros, O'Brien Mary E R, Popat Sanjay, Bhosle Jaishree, Yap Timothy A, de Bono Johann, Banerji Udai
The Lung Unit, Department of Medicine, The Royal Marsden, Sutton, United Kingdom.
The Drug Development Unit, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
PLoS One. 2017 Oct 5;12(10):e0186106. doi: 10.1371/journal.pone.0186106. eCollection 2017.
We investigated PD-L1 changes in response to MEK and AKT inhibitors in KRAS mutant lung adenocarcinoma (adeno-NSCLC). PD-L1 expression was quantified using immunofluorescence and co-culture with a jurkat cell-line transfected with NFAT-luciferase was used to study if changes in PD-L1 expression in cancer cell lines were functionally relevant. Five KRAS mutant cell lines with high PD-L1 expression (H441, H2291, H23, H2030 and A549) were exposed to GI50 inhibitor concentrations of a MEK inhibitor (trametinib) and an AKT inhibitor (AZD5363) for 3 weeks. Only 3/5 (H23, H2030 and A549) and 2/5 cell lines (H441 and H23) showed functionally significant increases in PD-L1 expression when exposed to trametinib or AZD5363 respectively. PD-L1 overexpression is not consistent and is unlikely to be an early mechanism of resistance to KRAS mutant adeno-NSCLC treated with MEK or AKT inhibitors.
我们研究了KRAS突变型肺腺癌（腺性非小细胞肺癌）中程序性死亡受体配体1（PD-L1）对MEK和AKT抑制剂的反应变化。使用免疫荧光法定量PD-L1表达，并与转染了活化T细胞核因子荧光素酶的Jurkat细胞系共培养，以研究癌细胞系中PD-L1表达的变化是否具有功能相关性。将5个高表达PD-L1的KRAS突变细胞系（H441、H2291、H23、H2030和A549）暴露于MEK抑制剂（曲美替尼）和AKT抑制剂（AZD5363）的半数抑制浓度（GI50）下3周。当分别暴露于曲美替尼或AZD5363时，只有3/5（H23、H2030和A549）和2/5的细胞系（H441和H23）显示出PD-L1表达有功能上的显著增加。PD-L1的过表达并不一致，不太可能是KRAS突变型腺性非小细胞肺癌对MEK或AKT抑制剂产生耐药性的早期机制。
