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

Abstract

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 in vitro and in vivo. 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 in vitro and Vem-resistant melanoma tumor growth in vivo 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.

MitoCur‐1 induces ferroptosis to reverse vemurafenib resistance in melanoma through inhibition of USP14

“…MitoCur‐1 is a curcumin analog that, indeed, we found its potential to cause apoptosis and cell cycle arrest in tumor cells, thereby reversing vem resistance in melanoma cells. Of note, baseline apoptosis level looks a little bit higher in vem‐resistant A375 cells compared with A375 cells (Figure 6c), which were observed in our previous study (Cui et al., 2021). This may result from “gain‐of function” of drug resistance property.…”

“…However, the drug resistance is a pressing concern. Many novel compounds are invented from the lab to overcome this issue, including tubulin inhibitor VERU‐111 (Cui et al., 2021; Wang et al., 2014).…”

“…Therefore, it is very necessary to find a new anti‐melanoma drug for the therapy of melanoma. We previously tested combination regimen of tubulin inhibitor VERU‐111 and vem (Cui et al., 2021), as well as ubiquitin‐specific protease 14 (USP14) selective inhibitor b‐AP15 combination with vem (Wu et al., 2022), both of which have showed profound therapeutic effects in overcoming vem resistance in both melanoma cells and melanoma xenograft tumor‐bearing nude mice. Most importantly, we found that vem‐resistant melanoma cell lines highly expressed E3 ligase SKP2 (S‐phase kinase‐associated protein 2) and DUB (Deubiquitinase) enzyme USP14, and we have demonstrated that USP14 directly interacts and stabilizes SKP2, which contributes to vem resistance.…”

Small-molecule compounds inhibiting S-phase kinase-associated protein 2: A review

“…Combined use of both inhibitors is effective in treating vemurafenib-resistant melanoma ( Wu et al, 2022 ). In addition, the combination of tubulin inhibitor VERU-111 and vemurafenib also inhibited vemurafenib-resistant melanoma effectively by inhibiting tubulin protein and Skp2 protein together ( Cui et al, 2021 ). Another example, the SCF Skp2 components related to BTZ resistance, and combined use of BTZ and Skp2 inhibitor inhibits BTZ-resistant multiple myeloma growth, rendering targeting SCF Skp2 as a strategy to overcome therapeutic resistance in multiple myeloma.…”

Combination of Paclitaxel and PXR Antagonist SPA70 Reverses Paclitaxel-Resistant Non-Small Cell Lung Cancer

“…One-way ANOVA was used to statistically compare tumor size and body weight for in vivo xenograft study. Tumor growth inhibition (TGI) was calculated according to the method which was previously reported [41].…”