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

Yafang Wang; Mingyue Yao; Cheng Li; Kexin Yang; Xiaolong Qin; Lansong Xu; Shangxuan Shi; Chengcheng Yu; Xiangjun Meng; Chengying Xie

doi:10.1186/s40164-023-00466-3

Targeting ST8SIA6-AS1 counteracts KRAS^G12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling

Exp Hematol Oncol. 2023 Dec 16;12(1):105. doi: 10.1186/s40164-023-00466-3.

Authors

Yafang Wang^#¹, Mingyue Yao^#^{1

2

3}, Cheng Li^{1

4}, Kexin Yang^{4

5}, Xiaolong Qin^{1

4}, Lansong Xu^{1

2

3}, Shangxuan Shi^{1

4}, Chengcheng Yu^{3

5}, Xiangjun Meng^{6

7

8}, Chengying Xie^{9

10

11}

Affiliations

¹ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China.
² Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), 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, People's Republic of China.
⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
⁵ Lingang Laboratory, 319 Yueyang Road, 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.
⁹ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China. xiecy@lglab.ac.cn.
¹⁰ School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. xiecy@lglab.ac.cn.
¹¹ Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China. xiecy@lglab.ac.cn.

^# Contributed equally.

Abstract

Background: KRAS^G12C inhibitors (KRAS^G12Ci) 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^G12Ci-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^G12Ci sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRAS^G12Ci. 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^G12Ci. 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^G12Ci resistance.

Conclusions: Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRAS^G12Ci and represents a promising therapeutic target for combination strategies with KRAS^G12Ci in the treatment of KRAS^G12C-mutant cancers.

Keywords: Drug resistance; KRASG12C; LncRNA; PLK1; ST8SIA6-AS1; c-Myc.

Abstract

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