1. Academic Validation
  2. LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells

LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells

  • Int J Med Sci. 2021 Jan 29;18(6):1456-1464. doi: 10.7150/ijms.51256.
Yongfang Ma 1 2 Ruyue Xu 1 2 Xueke Liu 1 3 Yinci Zhang 1 2 Li Song 1 2 Shuyu Cai 1 2 Shuping Zhou 1 Yinghai Xie 1 Amin Li 1 2 Weiya Cao 1 2 Xiaolong Tang 1 2


  • 1 Medical school, Anhui University of Science and Technology, Huainan 232001, China.
  • 2 Institute of Environment-friendly Materials and Occupational Health of Anhui University of Science and Technology (Wuhu), Wuhu, 241003, China.
  • 3 Department of Clinical Laboratory Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China.

Background: Sorafenib, an oral multi-kinase inhibitor of rapidly accelerated fibrosarcoma; vascular endothelial growth factor receptor-2/3, platelet-derived growth factor receptor, c-Kit, and Flt-3 signaling, is approved for treatment of advanced hepatocellular carcinoma (HCC). However, the benefit of sorafenib is often diminished because of acquired resistance through the reactivation of ERK signaling in sorafenib-resistant HCC cells. In this work, we investigated whether adding LY3214996, a selective ERK1/2 inhibitor, to sorafenib would increase the anti-tumor effectiveness of sorafenib to HCC cells. Methods: The Huh7 cell line was used as a cell model for treatment with sorafenib, LY3214996, and their combination. Phosphorylation of the key kinases in the Ras/Raf/MAPK and PI3K/Akt pathways, protein expression of the cell cycle, and Apoptosis migration were assessed with western blot. MTT and colony-formation assays were used to evaluate cell proliferation. Wound-healing assay was used to assess cell migration. Cell cycle and Apoptosis analyses were conducted with flow cytometry. Results: LY3214996 decreased phosphorylation of the Ras/Raf/MAPK and PI3K/Akt pathways, including p-c-Raf, p-P90RSK, p-S6K and p-eIF4EBP1 activated by sorafenib, despite increased p-ERK1/2 levels. LY3214996 increased the anti-proliferation, anti-migration, cell-cycle progression, and pro-apoptotic effects of sorafenib on Huh7R cells. Conclusions: Reactivation of ERK1/2 appears to be a molecular mechanism of acquired resistance of HCC to sorafenib. LY3214996 combined with sorafenib enhanced the anti-tumor effects of sorafenib in HCC. These findings form a theoretical basis for trial of LY3214996 combined with sorafenib as second-line treatment of sorafenib-resistant in advanced HCC.


LY3214996; Ras/Raf/MAPK pathway; acquired resistance; hepatocellular carcinoma; sorafenib.