BI-2865, a pan-KRAS inhibitor, reverses the P-glycoprotein induced multidrug resistance in vitro and in vivo

作者：Qihong Yang, Kenneth K.W. To, Guilin Hu, Kai Fu, Chuan Yang, Shuangli Zhu, Can Pan, Fang Wang, Ke-Wang Luo, Liwu Fu · 发表于：Cell Communication and Signaling · 年份：2024 · DOI：10.1186/s12964-024-01698-4 · 被引用次数：14 · 研究领域：Drug Transport and Resistance Mechanisms、Protein Kinase Regulation and GTPase Signaling、Heat shock proteins research

Abstract Background Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was approved by FDA to date. Here, we will investigate the effect of BI-2865, a pan-KRAS inhibitor, on reversing MDR induced by P-gp, BCRP and MRP1 in vitro and in vivo, and its reversal mechanisms will be explored. Methods The cytotoxicity of BI-2865 and its MDR removal effect in vitro were tested by MTT assays, and the corresponding reversal function in vivo was assessed through the P-gp mediated KBv200 xenografts in mice. BI-2865 induced alterations of drug discharge and reservation in cells were estimated by experiments of Flow cytometry with fluorescent doxorubicin, and the chemo-drug accumulation in xenografts’ tumor were analyzed through LC-MS. Mechanisms of BI-2865 inhibiting P-gp substrate’s efflux were analyzed through the vanadate-sensitive ATPase assay, [ 125 I]-IAAP-photolabeling assay and computer molecular docking. The effects of BI-2865 on P-gp expression and KRAS-downstream signaling were detected via Western blotting, Flow cytometry and/or qRT-PCR. Subcellular localization of P-gp was visualized by Immunofluorescence. Results We found BI-2865 notably fortified response of P-gp-driven MDR cancer cells to the administration of chemo-drugs including paclitaxel, vincristine and doxorubicin, while such an effect was not observed in their parental sensitive cells and BCRP or MRP1-dri...