Theranostics 2020; 10(21):9721-9740. doi:10.7150/thno.44342

Research Paper

HI-511 overcomes melanoma drug resistance via targeting AURKB and BRAF V600E

Xiaoyu Chang1,2*, Tianshun Zhang1*, Qiushi Wang1*, Moeez Ghani Rathore1, Kanamata Reddy1, Hanyong Chen1, Seung Ho Shin1, Wei-ya Ma1, Ann M Bode1, Zigang Dong1,2✉

1. The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA.
2. Program in Bioinformatics and Computational Biology, University of Minnesota, Minneapolis, MN 55455, USA.
*These authors contributed equally to this work.

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Citation:
Chang X, Zhang T, Wang Q, Rathore MG, Reddy K, Chen H, Shin SH, Ma Wy, Bode AM, Dong Z. HI-511 overcomes melanoma drug resistance via targeting AURKB and BRAF V600E. Theranostics 2020; 10(21):9721-9740. doi:10.7150/thno.44342. Available from http://www.thno.org/v10p9721.htm

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Abstract

Rationale: Melanoma is an aggressive tumor of the skin and 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, and survival rate analysis were utilized to identify a candidate target. An anchorage-independent cell growth assay, flow cytometry, Western blot, and a xenograft mouse model were used to study the function of Aurora kinase B (AURKB) in both drug-sensitive and drug-resistant melanoma. Next, HI-511, a novel dual-target inhibitor targeting both AURKB and BRAF V600E, was designed and examined by an in vitro kinase assay. Methods as indicated above in addition to a BRAF V600E/PTEN-loss melanoma mouse model were used to demonstrate the effect of HI-511 on melanoma development in vitro and in vivo.

Results: AURKB is highly expressed in melanoma and especially in vemurafenib-resistant melanoma and the expression was correlated with patient survival rate. Knocking down AURKB inhibited cell growth and induced apoptosis in melanoma, which was associated with the BRAF/MEK/ERKs and PI3-K/AKT signaling pathways. Importantly, we found that HI-511, a novel dual-target inhibitor against AURKB and BRAF V600E, suppresses both vemurafenib-sensitive and vemurafenib-resistant melanoma growth in vitro and in vivo by inducing apoptosis and mediating the inhibition of the BRAF/MEK/ERKs and PI3K/AKT signaling pathways.

Conclusion: AURKB is a potential target for melanoma treatment. HI-511, a novel dual-target inhibitor against both AURKB and BRAF V600E, could achieve durable suppression of melanoma growth, even drug-resistant melanoma growth.

Keywords: HI-511, AURKB, BRAF V600E, vemurafenib-resistant melanoma, melanoma