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
Source
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.
References63
Newest
#1Otto PulkkinenH-Index: 7
#2Prson Gautam (UH: University of Helsinki)H-Index: 16
Last. Tero AittokallioH-Index: 55
view all 4 authors...
Combinatorial therapies are required to treat patients with advanced cancers that have become resistant to monotherapies through rewiring of redundant pathways. Due to a massive number of potential drug combinations, there is a need for systematic approaches to identify safe and effective combinations for each patient, using cost-effective methods. Here, we developed an exact multiobjective optimization method for identifying pairwise or higher-order combinations that show maximal cancer-selecti...
2 CitationsSource
#1Hongmei Cui (UTHSC: University of Tennessee Health Science Center)H-Index: 5
#2Kinsie E. Arnst (UTHSC: University of Tennessee Health Science Center)H-Index: 7
view all 4 authors...
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 ...
5 CitationsSource
#1Foyez Mahmud (UTHSC: University of Tennessee Health Science Center)H-Index: 1
#2Shanshan Deng (UTHSC: University of Tennessee Health Science Center)H-Index: 5
Last. Wei Li (UTHSC: University of Tennessee Health Science Center)H-Index: 54
view all 5 authors...
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...
3 CitationsSource
#1Lin Feng (Shaanxi University of Chinese Medicine)H-Index: 1
#2Jun Li (Shaanxi University of Chinese Medicine)H-Index: 2
Last. Xuan Qu (Shaanxi University of Chinese Medicine)H-Index: 2
view all 6 authors...
Abstract BRAFV600E mutation is frequently observed in melanoma, and contributes to tumor malignancy. Despite inhibition of BRAF causes a profound cell growth inhibition and a strong clinical benefit in BRAFV600E melanoma, acquired drug resistance is still the major hurdle. In this study, we demonstrate that BRAFV600E drives cell growth and glycolysis in melanoma cells but does so by a previously unappreciated mechanism that involves direct induction of Skp2. Skp2 is highly expressed in melanoma ...
2 CitationsSource
#1Hima Patel (UC: University of Cincinnati)H-Index: 3
#2Nour Yacoub (NEOMED: Northeast Ohio Medical University)H-Index: 1
Last. Joan T. Garrett (UC: University of Cincinnati)H-Index: 16
view all 7 authors...
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...
40 CitationsSource
#1Vivek K. Kashyap (UTHSC: University of Tennessee Health Science Center)H-Index: 8
#2Nirnoy Dan (UTHSC: University of Tennessee Health Science Center)H-Index: 6
Last. Subhash C. Chauhan (UTHSC: University of Tennessee Health Science Center)H-Index: 49
view all 14 authors...
Abstract In this study, we investigated the therapeutic efficacy of VERU-111 in vitro and in vivo model systems of cervical cancer. VERU-111 treatment inhibited cell proliferation and, clonogenic potential, induce accumulation of p53 and down regulated the expression of HPV E6/E7 expression in cervical cancer cells. In addition, VERU-111 treatment also decreased the expression of phosphorylation of Jak2 (TyR1007/1008) and STAT3 at Tyr705 and Ser727. VERU-111 treatment arrested cell cycle in the ...
3 CitationsSource
#1Shanshan Deng (UTHSC: University of Tennessee Health Science Center)H-Index: 5
#2Raisa Krutilina (UTHSC: University of Tennessee Health Science Center)H-Index: 8
Last. Wei Li (UTHSC: University of Tennessee Health Science Center)H-Index: 54
view all 10 authors...
Triple-negative breast cancer (TNBC) accounts for ~15% of breast cancer cases in the United States. TNBC has poorer overall prognosis relative to other molecular subtypes due to rapid onset of drug resistance to conventional chemotherapies and increased risk of visceral metastases. Taxanes like paclitaxel are standard chemotherapies that stabilize microtubules, but their clinical efficacy is often limited by drug resistance and neurotoxicities. We evaluated the preclinical efficacy of a novel, p...
9 CitationsSource
#1Hao Chen (UTHSC: University of Tennessee Health Science Center)H-Index: 10
#2Shanshan Deng (UTHSC: University of Tennessee Health Science Center)H-Index: 5
Last. Wei Li (UTHSC: University of Tennessee Health Science Center)H-Index: 54
view all 10 authors...
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...
14 CitationsSource
#1Qinghui Wang (UTHSC: University of Tennessee Health Science Center)H-Index: 9
#2Kinsie E. Arnst (UTHSC: University of Tennessee Health Science Center)H-Index: 7
Last. Wei Li (Sichuan University)H-Index: 54
view all 8 authors...
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 ...
13 CitationsSource
ABSTRACTIntroduction: Combination treatment with a BRAF inhibitor and MEK inhibitor is the standard of care for patients with advanced BRAFV600 mutation-positive melanoma. With the currently available combinations of dabrafenib plus trametinib and vemurafenib plus cobimetinib, median progression-free survival (PFS) of over 12 months has been achieved. However, treatment resistance and disease recurrence remain a clinical challenge.Areas covered: Encorafenib in combination with bimetinib offers a...
22 CitationsSource
Cited By0
Newest