Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma  

作　　者：Ming-zhao Gao Hong-bin Wang Xiang-ling Chen Wen-ting Cao Li Fu Yun Li Hai-tian Quan Cheng-ying Xie Li-guang Lou 

机构地区：[1]Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2]University of Chinese Academy of Sciences, Beijing 100049, China

出　　处：《Acta Pharmacologica Sinica》2019年第2期268-278,共11页中国药理学报（英文版）

基　　金：National Natural Science Foundation of China (No.81273546);Shanghai Science and Technology Committee (No. 14DZ2294100).

摘　　要：BRAF and MEK inhibitors have shown remarkable clinical efficacy in BRAF-mutant melanoma;however, most patients develop resistance, which limits the clinical benefit of these agents. In this study, we found that the human melanoma cell clones, A375-DR and A375-TR, with acquired resistance to BRAF inhibitor dabrafenib and MEK inhibitor trametinib, were cross resistant to other MAPK pathway inhibitors. In these resistant cells, phosphorylation of ribosomal protein S6 (rpS6) but not phosphorylation of ERK or p90 ribosomal S6 kinase (RSK) were unable to be inhibited by MAPK pathway inhibitors. Notably, knockdown of rpS6 in these cells effectively downregulated G1 phase-related proteins, including RB, cyclin D1, and CDK6, induced cell cycle arrest, and inhibited proliferation, suggesting that aberrant modulation of rpS6 phosphorylation contributed to the acquired resistance. Interestingly, RSK inhibitor had little effect on rpS6 phosphorylation and cell proliferation in resistant cells, whereas P70S6K inhibitor showed stronger inhibitory effects on rpS6 phosphorylation and cell proliferation in resistant cells than in parental cells. Thus regulation of rpS6 phosphorylation, which is predominantly mediated by BRAF/MEK/ERK/RSK signaling in parental cells, was switched to mTOR/P70S6K signaling in resistant cells. Furthermore, mTOR inhibitors alone overcame acquired resistance and rescued the sensitivity of the resistant cells when combined with BRAF/MEK inhibitors. Taken together, our findings indicate that RSK-independent phosphorylation of rpS6 confers resistance to MAPK pathway inhibitors in BRAF-mutant melanoma, and that mTOR inhibitor-based regimens may provide alternative strategies to overcome this acquired resistance.

关 键 词：BRAF-mutant MELANOMA MAPK pathway INHIBITORS acquired resistance P70S6K RSK rpS6 G1/G0 phase arrest mTOR inhibitor 

分 类 号：R[医药卫生]