HI-511 Overcomes Melanoma Drug Resistance via Targeting AURKB and BRAF V600E

Abstract

Background: Melanoma is an aggressive tumor of the skin. Drug resistance is still a major problem in melanoma therapy. Novel targets and effective agents to overcome drug resistant melanoma are urgently needed in clinical therapy. Methods: Gene Expression Omnibus (GEO) database analysis, pathway enrichment analysis, survival rate analysis were utilized to identify the candidate target. Anchorage-independent cell growth assay, flow cytometry, western blot and xenograft mouse model were conducted to study the function of AURKB in melanoma in both drug-sensitive and drug-resistant melanoma. Next, HI-511, a novel dual-target inhibitor of AURKB and BRAF V600E, was designed and confirmed by in vitro kinase assay. Anchorage-independent cell growth assay, flow cytometry. western blot, xenograft and BRAF V600E/PTEN-loss melanoma mouse models were conducted to demonstrate the effect of HI-511 on melanoma development in vitro and in vivo. Findings: AURKB is high expression in melanoma and even higher in vemurafenib-resistant melanoma, which correlated with patient's survival rate. Knocking down AURKB inhibits cells growth and induces apoptosis in melanoma, which is associated with BRAF/MEK/ERKs and PI3K/AKT signaling pathways. Importantly, we find HI-511 suppresses both vemurafenib-sensitive and vemurafenib-resistant melanoma in vitro and in vivo by inducing apoptosis and mediating the activation of BRAF/MEK/ERKs and PI3K/AKT signaling pathways. Interpretation: AURKB could be a potential target for melanoma treatment. HI-511, a novel dual-target inhibitor of both AURKB and BRAF V600E, could achieve durable suppression of melanoma, even drug-resistant melanoma. Funding Statement: This work was supported by the Hormel Foundation. Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: All studies were performed following guidelines approved by the University of Minnesota Institutional Animal Care and Use Committee (Minneapolis, MN).