Everolimus selectively targets vemurafenib resistant BRAFV600E melanoma cells adapted to low pH (original) (raw)
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Phase II Study of Everolimus in Metastatic Malignant Melanoma (NCCTG-N0377, Alliance)
The Oncologist, 2018
Lessons Learned Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma. Patients treated with 10 mg per day dose were most likely to require dose reductions. Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes. Background Everolimus (RAD-001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM). Methods This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16-week progression-free survival (PFS), overall survival (OS), and measures o...
mTOR inhibitor Everolimus-induced apoptosis in melanoma cells
Journal of Cell Communication and Signaling
Melanoma is the most aggressive, therapy-resistant skin cancer. The mammalian target of rapamycin (mTOR), the serine/ threonine kinase which integrates both intracellular and extracellular signals, plays a crucial role in coordinating the balance between the growth and death of cells. The object of this study is a comparison of the influence of mTOR inhibitor everolimus in the concentration range between 20 nM and 10 μM, used individually and in combination with selected downstream protein kinases inhibitors: LY294002 (PI3K), U0126 (ERK1/2), AS-703026 (MEK) and MK-2206 (AKT) on the expression of prosurvival proteins: p-Bcl-2 (S70), p-Bcl-2 (T56), Bcl-2, Bcl-xL, Mcl-1, activity of caspase-3, proliferation and induction of apoptosis in melanoma cells. Current results clearly show that the nanomolar concentration of the mTOR inhibitor everolimus in combination with the inhibitor of MAP kinase (AS-703026) or AKT kinase (MK-2206) is effective in inducing apoptosis and reducing proliferation of melanoma cells. The herein research results confirm the hypothesis on the important role of mTOR signaling in cancer progression, and gives hope that implementation of successful combination of its inhibitors will find recognition and application in cancer treatment in the near future.
Phase II Study of Temozolomide (TMZ) and Everolimus (RAD001) Therapy for Metastatic Melanoma
American Journal of Clinical Oncology, 2013
Objective-Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt-mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents [temozolomide (TMZ)] and inhibition of tumor angiogenesis. Methods-We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/ wk) and 200 mg/m 2 /d of TMZ for 5 days each cycle.
Scientific Reports, 2019
Although the utilization of selective BRAF V600E inhibitors is associated with improved overall survival in patients with metastatic melanoma, a growing challenge of drug resistance has emerged. CDC7 has been shown to be overexpressed and associated with poor prognosis in various cancers including melanoma. Thus, we aimed to elucidate the biological role of CDC7 in promoting Vemurafenib resistance and the anticipated benefits of dual targeting of BRAF V600E and CDC7 in melanoma cells. We performed exosomes-associated microRNA profiling and functional assays to determine the role of CDC7 in drug resistance using Vemurafenib-sensitive and resistant melanoma cells. Our results demonstrated that Vemurafenib-resistant cells exhibited a persistent expression of CDC7 in addition to prolonged activity of MCM2 compared to drug-sensitive cells. Reconstitution of miR-3613-3p in resistant cells downregulated CDC7 expression and reduced the number of colonies. Treatment of cells with low concentrations of CDC7 inhibitor TAK-931 sensitized resistant cells to Vemurafenib and reduced the number of cell colonies. Taken together, CDC7 overexpression and downregulation of miR-3613-3p were associated with Vemurafenib resistance in BRAF V600E-bearing melanoma cells. Dual targeting of CDC7 and BRAF V600E reduced the development of resistance against Vemurafenib. Further studies are warranted to investigate the clinical effect of targeting CDC7 in metastatic melanoma. BRAF is a driver oncogene in various human cancers including melanoma, and was the first described oncoprotein with serine/threonine kinase activity 1,2. Among all identified BRAF missense mutations, BRAF V600E with a single nucleotide transversion from valine to glutamate at position 600 is the most clinically prevalent mutation 3,4. The mutational activation of BRAF V600E increases BRAF kinase activity extremely higher than the wild-type BRAF, leading to a subsequent 4.6-fold persistent activation of ERK1/2 signaling cascade 5,6. The mutant BRAF V600E was identified as the bona fide transforming oncogene in malignant melanoma, contributing to 70% of melanoma cases 3. Due to the potential contribution of mutationally dysregulated kinases in melanomagenesis and progression, BRAF V600E was identified as a promising target for clinically effective therapeutics, including Vemurafenib 7. Vemurafenib (Zelboraf ® , PLX4032), is a potent specific inhibitor of BRAF V600E , which was the first FDA approved drug against BRAF-mutated metastatic melanoma in 2011 8. Vemurafenib effectively blocks cell growth, angiogenesis, invasion and metastasis and induce tumor cell death in BRAF V600E-associated melanomas 7,9-11. Despite the remarkable clinical benefits associated with the selective BRAF V600E inhibition by Vemurafenib, emergence of drug resistance hampered the treatment of metastatic melanoma. Approximately
Cancers, 2021
Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. High-resolution and high-throughput technology has led to the identification of distinct mutational signatures and their downstream alterations in several key pathways that contribute to melanomagenesis. This has enabled the development of individualized treatments by targeting specific molecular alterations that are vital for cancer cell survival, which has resulted in improved outcomes in several cancers, including melanomas. To date, BRAF and MEK inhibitors remain the only approved targeted therapy with a high level of evidence in BRAFV600E/K mutant melanomas. The lack of approved precision drugs in melanomas, relative to other cancers, despite harboring one of the highest rates of somatic mutations, ...
Journal of Cancer, 2018
BRAF mutations occur in about 50% of melanoma patients. FDA approved BRAF and MEK inhibitors have improved the prognosis of patients with BRAF mutations. However, all responders develop resistance typically within one year of treatment. Recent observations demonstrate that BRAF inhibitors induce reactive oxygen species (ROS) in melanoma cells. A100, identified from a library screen, is a ROS-activated prodrug that self-cyclizes into a stable bicyclic ring and causes DNA double strand breaks. We proposed to examine if ROS activated therapy will inhibit tumor growth and evade resistance to BRAF inhibitors. In this study, the BRAF inhibitor dabrafenib was used to generate resistant cell lines (A375DR, SK-MEL-24DR and WM-115DR). Flow cytometry experiments showed that ROS levels are increased in these dabrafenib-resistant cells as compared to parental cells, assessed by both the H2DCFDA and MitoSOX assays. Furthermore, we observed that resistant cells had increased levels of the mitochondrial enzymes SOD2 and PRDX1, which function to reduce ROS levels in the mitochondria. We found that A100 sensitized the resistant melanoma cells to dabrafenib and induced DNA damage. Co-treatment of both A100 and dabrafenib significantly suppressed in vitro cell proliferation and three-dimensional (3D) matrigel growth. This study suggests that the combination of A100 with a BRAF inhibitor could be a potential strategy to treat melanoma patients with BRAF mutations.
Oncotarget, 2016
The majority of human melanomas bears BRAF mutations and thus is treated with inhibitors of BRAF, such as vemurafenib. While patients with BRAF mutations often demonstrate an initial dramatic response to vemurafenib, relapse is extremely common. Thus, novel agents are needed for the treatment of these aggressive melanomas. Honokiol is a small molecule compound derived from Magnolia grandiflora that has activity against solid tumors and hematopoietic neoplasms. In order to increase the lipophilicity of honokiol, we have synthesized honokiol DCA, the dichloroacetate ester of honokiol. In addition, we synthesized a novel fluorinated honokiol analog, bis-trifluoromethyl-bis-(4-hydroxy-3-allylphenyl) methane (hexafluoro). Both compounds exhibited activity against A375 melanoma in vivo, but honokiol DCA was more active. Gene arrays comparing treated with vehicle control tumors demonstrated induction of the respiratory enzyme succinate dehydrogenase B (SDHB) by treatment, suggesting that o...
Effect of dabrafenib on melanoma cell lines harbouring the BRAFV600D/R mutations
BMC Cancer, 2013
Background: Conventional therapeutic agents are largely unsatisfactory into the treatment of malignant melanoma. Recently, an innovative approach based on inhibitors of the mutated BRAF gene (which represents the most prevalent alteration in melanoma patients) appears very promising from the clinical point of view. On this regard, a new compound, dabrafenib (GSK2118436), has been demonstrated to be effective in patients carrying the BRAFV600E/K mutations. We here tested dabrafenib for its capability to inhibit cell growth on primary melanoma cell lines, established from patients' tumour tissues and carrying the BRAFV600D/R mutations. Methods: Three melanoma cell lines were tested: M257 wild-type BRAF, LCP BRAFV600R and WM266 BRAFV600D. The MTT assays were performed using standardized approaches. To evaluate the inhibition of MAPK pathway and the consequent inhibition of cellular proliferation, the phosphorylation of ERK was examined by Western Blot analysis performed on total protein extracts from cell lines after treatment with dabrafenib. Results: Our experiments demonstrated an effective action of Dabrafenib (GSK2118436) and the inhibition of MAPK pathway in melanoma cell lines carrying BRAFV600D/R mutations. Conclusion: These results could be helpful to enlarge the number of melanoma patients who may benefit of a more effective targeted treatment.
mTOR inhibitor everolimus reduces invasiveness of melanoma cells
Human Cell
The mammalian target of rapamycin (mTOR) plays a key role in several cellular processes: proliferation, survival, invasion, and angiogenesis, and therefore, controls cell behavior both in health and in disease. Dysregulation of the mTOR signaling is involved in some of the cancer hallmarks, and thus the mTOR pathway is an important target for the development of a new anticancer therapy. The object of this study is recognition of the possible role of mTOR kinase inhibitors—everolimus single and in combination with selected downstream protein kinases inhibitors: LY294002 (PI3 K), U0126 (ERK1/2), GDC-0879 (B-RAF), AS-703026 (MEK), MK-2206 (AKT), PLX-4032 (B-RRAF) in cell invasion in malignant melanoma. Treatment of melanoma cells with everolimus led to a significant decrease in the level of both phosphorylated: mTOR (Ser2448) and mTOR (Ser2481) as well as their downstream effectors. The use of protein kinase inhibitors produced a significant decrease in metalloproteinases (MMPs) activi...