AUTHOR=Cui Hongmei , Wang Qinghui , Miller Duane D. , Li Wei 

TITLE=The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.637098

DOI=10.3389/fphar.2021.637098

ISSN=1663-9812

ABSTRACT=Melanoma is one of the deadliest skin cancers having a five-year survival rate of around 15–20%. An overactivated MAPK/Akt pathway is well-established in BRAF mutant melanoma. Vemurafenib (Vem) was the first FDA-approved BRAF inhibitor and gained great clinical success in treating late-stage melanoma. However, most patients acquired resistance to Vem within 6~9 months. Therefore, developing a new treatment strategy to overcome Vem-resistance is highly significant.
Our previous study reported that the combination of a tubulin inhibitor ABI-274 with Vem showed a great synergistic effect to sensitize Vem-resistant melanoma both in vitro and in vivo. In the present study, we unveiled that VERU-111, an orally bioavailable inhibitor of α and β tubulin, is highly potent against Vem-resistant melanoma cells. The combination of Vem and VERU-111 resulted in a dramatically enhanced inhibitory effect on cancer cells in vitro and Vem-resistant melanoma growth in vivo compared with either single treatment. Further molecular signaling analyses demonstrated that in addition to ERK/AKT pathway, Skp2 E3 ligase also plays a critical role in Vem-resistant mechanisms. Knockout of Skp2 diminished oncogene Akt expression and contributed to the synergistic inhibitory effect of Vem and VERU-111. Our results indicate a treatment combination of VERU-111 and Vem can overcome Vem-resistance for melanoma patients harboring BRAF (V600E) mutation.