aberrantmodulationofribosomalproteins6phosphorylationconfersacquiredresistancetomapkpathwayinhibitorsinbrafmutantmelanoma

	aberrantmodulationofribosomalproteins6phosphorylationconfersacquiredresistancetomapkpathwayinhibitorsinbrafmutantmelanoma
	Mingzhao Gao 1; Hongbin Wang 1; Xiangling Chen 1; Wenting Cao 1; Li Fu 1; Yun Li 1; Haitian Quan 1; Chengying Xie 1; Liguang Lou 1
刊名	中国药理学报英文版
	2019
卷号	040 期号:002 页码:268
关键词	BRAF-mutant melanoma MAPK pathway inhibitors acquired resistance P70S6K RSK rpS6 G1/G0 phase arrest mTOR inhibitor
ISSN号	1671-4083
英文摘要	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.
资助项目	[National Natural Science Foundation of China] ; [Shanghai Science and Technology Committee]
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/283002]
专题	中国科学院上海药物研究所
作者单位	1.中国科学院上海药物研究所 2.中国科学院大学
推荐引用方式 GB/T 7714	Mingzhao Gao,Hongbin Wang,Xiangling Chen,et al. aberrantmodulationofribosomalproteins6phosphorylationconfersacquiredresistancetomapkpathwayinhibitorsinbrafmutantmelanoma[J]. 中国药理学报英文版,2019,040(002):268.
APA	Mingzhao Gao.,Hongbin Wang.,Xiangling Chen.,Wenting Cao.,Li Fu.,...&Liguang Lou.(2019).aberrantmodulationofribosomalproteins6phosphorylationconfersacquiredresistancetomapkpathwayinhibitorsinbrafmutantmelanoma.中国药理学报英文版,040(002),268.
MLA	Mingzhao Gao,et al."aberrantmodulationofribosomalproteins6phosphorylationconfersacquiredresistancetomapkpathwayinhibitorsinbrafmutantmelanoma".中国药理学报英文版 040.002(2019):268.