MRTX849逆转ABCB1介导的肿瘤多药耐药

MRTX849 Reverses ABCB1-Mediated Multidrug Resistance in Cancer Cells

P-糖蛋白(ABCB1/P-gp)过表达是导致肿瘤多药耐药(multidrug resistance,MDR)的主要因素之一。因此,寻找有效的药物来克服ABCB1介导的多药耐药非常重要。MRTX849是一种突变选择性的KRAS G12C共价抑制剂,用于非小细胞肺癌及肠癌的治疗。该实验研究了MRTX849是否能逆转ABCB1介导的多药耐药及其作用机制。逆转实验结果显示,MRTX849能显著逆转ABCB1介导的多药耐药,而不会影响ABCG2介导的多药耐药。Western blot及免疫荧光实验结果显示,MRTX849不会影响ABCB1在细胞内的表达及定位。进一步的研究发现,MRTX849抑制了ABCB1外排功能,导致细胞内药物蓄积水平的增加,从而逆转多药耐药。此外,分子对接实验显示,MRTX849和ABCB1呈现了良好的亲和能力。总之,该研究表明MRTX849逆转了ABCB1介导的多药耐药,为化疗抵抗的肿瘤患者提供了一种新的临床治疗策略。

P-glycoprotein(ABCB1/P-gp)overexpression is one of the major factors leading to MDR(multidrug resistance)in cancers.Therefore,it is important to find effective drugs to overcome ABCB1-mediated MDR.MRTX849 is a mutation-selective KRAS G12C covalent inhibitor for the treatment of non-small cell lung cancer and colorectal cancer.This study aimed to investigate whether MRTX849 could reverse ABCB1-mediated MDR and the underlying mechanism.The results of reversal assay showed that MRTX849 significantly reversed ABCB1-mediated MDR without affecting ABCG2-mediated MDR.The results of Western blot and immunofluorescence assays suggested that MRTX849 did not affect the intracellular expression and localization of ABCB1.Further studies revealed that MRTX849 inhibited ABCB1 efflux function,leading to an increase in intracellular drug accumulation levels,thereby reversing MDR.In addition,molecular docking analysis showed that MRTX849 and ABCB1 presented good affinity.In conclusion,this study demonstrated that MRTX849 reversed ABCB1-mediated MDR,providing a new clinical treatment strategy for chemotherapy-resistant tumor patients.