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

• Published in: Frontiers in pharmacology Vol. 12; p. 637098
• Main Authors: Cui, Hongmei, Wang, Qinghui, Miller, Duane D, Li, Wei
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 25-03-2021
• Subjects: akt; ERK; melanoma; Pharmacology; skp2; vemurafenib-resistance; VERU-111; melanoma; vemurafenib-resistance; akt; VERU-111; ERK; skp2
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2021.637098

Melanoma is one of the deadliest skin cancers having a five-year survival rate 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 develop 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 significant synergistic effect to sensitize Vem-resistant melanoma both
and
. In the present study, we unveiled that VERU-111, an orally bioavailable inhibitor of α and β tubulin that is under clinical development, 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
and Vem-resistant melanoma tumor growth
compared with single-agent 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 holds a great promise to overcome Vem-resistance for melanoma patients harboring BRAF (V600E) mutation.