Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling
文献类型：期刊论文
| 作者 | Wang, Yafang8; Yao, Mingyue6,7,8; Li, Cheng5,8; Yang, Kexin4,5; Qin, Xiaolong5,8; Xu, Lansong6,7,8; Shi, Shangxuan5,8; Yu, Chengcheng4,6; Meng, Xiangjun1,2,3; Xie, Chengying4,5,8 |
| 刊名 | EXPERIMENTAL HEMATOLOGY & ONCOLOGY
 |
| 出版日期 | 2023-12-16 |
| 卷号 | 12期号:1页码:22 |
| 关键词 | KRAS(G12C) c-Myc PLK1 LncRNA ST8SIA6-AS1 Drug resistance |
| DOI | 10.1186/s40164-023-00466-3 |
| 通讯作者 | Xie, Chengying(xiecy@lglab.ac.cn) |
| 英文摘要 | Background KRAS(G12C) inhibitors (KRAS(G12C)i) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRAS(G12C)-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 KRAS(G12C)i-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 KRAS(G12C)i sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRAS(G12C)i. 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 KRAS(G12C)i. ST8SIA6-AS1 was found significantly upregulated in resistant cells and facilitated the proliferation of KRAS(G12C)-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 KRAS(G12C)i resistance.Conclusions Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRAS(G12C)i and represents a promising therapeutic target for combination strategies with KRAS(G12C)i in the treatment of KRAS(G12C)-mutant cancers. |
| WOS关键词 | POLO-LIKE KINASE-1 ; PANCREATIC-CANCER ; MYELOID-LEUKEMIA ; GENE-EXPRESSION ; CELL-LINES ; MYC ; GROWTH ; PROLIFERATION ; SUPPRESSION ; DEGRADATION |
| 资助项目 | Natural Science foundation of Shanghai, China ; Molecular imaging platform of ShanghaiTech University ; Discovery technology platform of Shanghai Institute for Advanced Immunochemical Studies |
| WOS研究方向 | Oncology ; Hematology |
| 语种 | 英语 |
| 出版者 | BMC |
| WOS记录号 | WOS:001125647900001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/308301]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Xie, Chengying |
| 作者单位 | 1.China Shanghai Key Lab Gut Microecol & Associated, Shanghai 200001, Peoples R China 2.Shanghai Jiao Tong Univ, China Ctr Digest Dis Res & Clin Translat, Shanghai 200001, Peoples R China 3.Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Sch Med, Gastroenterol, Shanghai 200001, Peoples R China 4.Lingang Lab, 319 Yueyang Rd, Shanghai 200031, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 7.Univ Sci & Technol China, USTC, Affiliated Hosp 1, Anhui Prov Hosp,Div Life Sci & Med, Hefei, Anhui, Peoples R China 8.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Yafang,Yao, Mingyue,Li, Cheng,et al. Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling[J]. EXPERIMENTAL HEMATOLOGY & ONCOLOGY,2023,12(1):22. |
| APA | Wang, Yafang.,Yao, Mingyue.,Li, Cheng.,Yang, Kexin.,Qin, Xiaolong.,...&Xie, Chengying.(2023).Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling.EXPERIMENTAL HEMATOLOGY & ONCOLOGY,12(1),22. |
| MLA | Wang, Yafang,et al."Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling".EXPERIMENTAL HEMATOLOGY & ONCOLOGY 12.1(2023):22. |
入库方式： OAI收割
来源：上海药物研究所
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