Hi-511 Inhibits Both BRAF and AURKB To Overcome Malignant Melanoma Drug Resistance and Metastasis

Abstract

Melanoma is an aggressive tumor of the skin. Although BRAF V600E inhibitors have been developed to treat melanoma, drug resistance and metastasis are still the major problems in melanoma therapy. Novel targets and effective agents to overcome drug resistant melanoma and reduce metastasis are urgently needed in clinical therapy. In this study, AURKB was defined as the target for melanoma therapy in an effort to overcome drug resistance. Notably, HI-511, a novel dual-target inhibitor for AURKB and BRAF V600E, inhibits development of both drug-sensitive and drug-resistant melanoma. We analyzed the Gene Expression Omnibus (GEO) database, utilized gene editing, and a xenograft mouse model to show AURKB is crucial for development of both drug-sensitive and drug-resistant melanoma. Inhibition of AURKB suppresses the cell growth and the rate of induced apoptosis in melanoma. Knocking down expression of AURKB decreased activation of the BRAF/MEK/ERKs and PI3K/AKT signaling pathways. Notably, a novel AURKB and BRAF V600E dual-target inhibitor HI-511 was developed. HI-511 strongly suppresses development of vemurafenib-sensitive and vemurafenib-resistant melanoma in vitro and in vivo, which is evidenced by in vitro kinase assays, cell base studies, xenograft mouse models and the BRAF V600E/PTEN-loss melanoma mouse model. Moreover, we also analysis the metastatic melanoma database and utilized the wound healing assay and a luciferase-linked xenograft mouse model to demonstrate HI-511 could reduce melanoma metastasis. Overall, AURKB could be a potential target for melanoma treatment and could overcome the resistance to BRAF V600E inhibitor and reduce melanoma metastasis. HI-511 is a novel dual-target inhibitor for both AURKB and BRAF V600E and could achieve durable suppression of melanoma, even drug-resistant melanoma and metastatic melanoma.