2. Academic Validation
  3. Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling

Targeting ST8SIA6-AS1 counteracts KRASG12C 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.
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

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. [email protected].
  • 10 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  • 11 Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China. [email protected].
  • # Contributed equally.
PMID: 38104151 DOI: 10.1186/s40164-023-00466-3
Abstract

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. ST8SIA6-AS1 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.

Keywords

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

Figures
Products