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

Published on Mar 25, 2021in Frontiers in Pharmacology4.225
· DOI :10.3389/FPHAR.2021.637098
Hongmei Cui5
Estimated H-index: 5
(UTHSC: University of Tennessee Health Science Center),
Qinghui Wang9
Estimated H-index: 9
+ 1 AuthorsWei Li54
Estimated H-index: 54
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.
#1Otto PulkkinenH-Index: 7
#2Prson Gautam (UH: University of Helsinki)H-Index: 16
Last. Tero AittokallioH-Index: 55
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Paclitaxel (PTX) is a first-line drug for late-stage non-small cell lung cancer (NSCLC) patients who do not benefit from targeted therapy or immunotherapy. However, patients invariably develop resistance to PTX upon prolonged treatments. Although diverse mechanisms leading to PTX resistance have been well-documented in the literature, strategies to overcome PTX resistance in NSCLC based on these mechanisms are still challenging. In this article, we reviewed recent advancements elucidating major ...
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Abstract Lung cancer is the most common cause of cancer associated mortality. Chemotherapeutic agents, such as paclitaxel, are important treatment options but drug resistance often develops upon prolonged use. We report here the preclinical evaluation of a new orally available tubulin inhibitor, VERU-111, which can overcome several ABC-transporter mediated multi-drug resistance associated with taxane treatment. In vitro, VERU-111 prevents cell proliferation, invasion, migration and colony format...
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#2Jun Li (Shaanxi University of Chinese Medicine)H-Index: 2
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Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within th...
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We recently reported the crystal structure of tubulin in complex with a colchicine binding site inhibitor (CBSI) ABI-231, having 2-aryl-4-benzoyl-imidazole (ABI). Based on this and additional crystal structures, here we report the structure activity relationships study of a novel series of pyridine analogues of ABI-231, with compound 4v being the most potent one (average IC50 ~1.8 nM) against a panel of cancer cell lines. We determined the crystal structures of another potent CBSI ABI-274 and 4v...
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ABI-231 is a potent, orally bioavailable tubulin inhibitor that interacts with the colchicine binding site and is currently undergoing clinical trials for prostate cancer. Guided by the crystal structure of ABI-231 in complex with tubulin, we performed structure–activity relationship studies around the 3-indole moiety that led to the discovery of several potent ABI-231 analogues, most notably 10ab and 10bb. The crystal structures of 10ab and 10bb in complex with tubulin confirmed their improved ...
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