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

Xiaoyu Chang, Tianshun Zhang, Qiushi Wang, Moeez Ghani Rathore, Kanamata Reddy, Hanyong Chen, Seung Ho Shin, Wei-Ya Ma, Ann M Bode, Zigang Dong

Theranostics 2020

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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. © The author(s).

Citation

Xiaoyu Chang, Tianshun Zhang, Qiushi Wang, Moeez Ghani Rathore, Kanamata Reddy, Hanyong Chen, Seung Ho Shin, Wei-Ya Ma, Ann M Bode, Zigang Dong. HI-511 overcomes melanoma drug resistance via targeting AURKB and BRAF V600E. Theranostics. 2020;10(21):9721-9740