Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling
Ya‐Fang Wang, Mingyue Yao, Cheng Li, Kexin Yang, Xiaolong Qin, Lansong Xu, Shangxuan Shi, Chengcheng Yu, Xiangjun Meng, Chengying Xie
Abstract
Abstract 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.