Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling

doi:10.1186/s40164-023-00466-3

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	Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling
	Yafang Wang1 ; Mingyue Yao 1,2,3; Cheng Li (李成)1,4 ; Kexin Yang4,5 ; Xiaolong Qin1,4 ; Lansong Xu 1,2,3; Shangxuan Shi1,4 ; Chengcheng Yu 3,5; Xiangjun Meng 6,7,8; Chengying Xie1,4,5
	2023-12-16
发表期刊	EXPERIMENTAL HEMATOLOGY & ONCOLOGY (IF:9.4[JCR-2023],8.3[5-Year])
ISSN	2162-3619
发表状态	已发表
DOI	10.1186/s40164-023-00466-3
摘要	Background KRASG12C inhibitors (KRASG12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRASG12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. This study aimed to identify the critical mediators and develop overcoming strategies. Methods By using RNA sequencing, RT-qPCR and immunoblotting, we identified and validated the upregulation of c-Myc activity and the amplification of the long noncoding RNA ST8SIA6-AS1 in KRASG12Ci-resistant cells. The regulatory axis ST8SIA6-AS1/Polo-like kinase 1 (PLK1)/c-Myc was investigated by bioinformatics, RNA fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and chromatin immunoprecipitation. Gain/loss-of-function assays, cell viability assay, xenograft models, and IHC staining were conducted to evaluate the anti-cancer effects of co-inhibition of ST8SIA6-AS1/PLK1 pathway and KRAS both in vitro and in vivo. Results KRASG12Ci sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRASG12Ci. PLK1 activation contributed to this ERK-independent c-Myc stability, which in turn directly induced PLK1 transcription, forming a positive feedback loop and conferring resistance to KRASG12Ci. ST8SIA6AS1 was found significantly upregulated in resistant cells and facilitated the proliferation of KRASG12C-mutant cancers. ST8SIA6-AS1 bound to Aurora kinase A (Aurora A)/PLK1 and promoted Aurora A-mediated PLK1 phosphorylation. Concurrent targeting of KRAS and ST8SIA6-AS1/PLK1 signaling suppressed both ERK-dependent and -independent c-Myc expression, synergistically led to cell death and tumor regression and overcame KRASG12Ci resistance. Conclusions Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRASG12Ci and represents a promising therapeutic target for combination strategies with KRASG12Ci in the treatment of KRASG12C-mutant cancers.
关键词	KRASG12C, c-Myc, PLK1, LncRNA, ST8SIA6-AS1, Drug resistance
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/415566
专题	免疫化学研究所生命科学与技术学院免疫化学研究所_特聘教授组_蒋华良组生命科学与技术学院_硕士生生命科学与技术学院_博士生
共同第一作者	Mingyue Yao
通讯作者	Chengying Xie
作者单位	1.Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, P. R. China 2.The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China 3.Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China 4.School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China 5.Lingang Laboratory, Shanghai 200031, China 6.Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China 7.China Center for Digestive Diseases Research and Clinical Translation of Shanghai Jiao Tong University, Shanghai 200001, China 8.China Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai 200001 China
第一作者单位	免疫化学研究所
通讯作者单位	免疫化学研究所; 生命科学与技术学院
第一作者的第一单位	免疫化学研究所
推荐引用方式 GB/T 7714	Yafang Wang,Mingyue Yao,Cheng Li ,et al. Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling[J]. EXPERIMENTAL HEMATOLOGY & ONCOLOGY,2023.
APA	Yafang Wang.,Mingyue Yao.,Cheng Li .,Kexin Yang.,Xiaolong Qin.,...&Chengying Xie.(2023).Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling.EXPERIMENTAL HEMATOLOGY & ONCOLOGY.
MLA	Yafang Wang,et al."Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling".EXPERIMENTAL HEMATOLOGY & ONCOLOGY (2023).