RSK2 promotes melanoma cell proliferation and vemurafenib resistance via upregulating cyclin D1
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BRAF inhibitors are commonly used in targeted therapies for melanoma patients harboring BRAFV600E mutant. Despite the benefit of vemurafenib therapy, acquired resistance during or after treatment remains a major obstacle in BRAFV600E mutant melanoma. Here we found that RSK2 is overexpressed in melanoma cells and the high expression of RSK2 indicates poor overall survival (OS) in melanoma patients. Overexpression of RSK2 leads to vemurafenib resistance, and the deletion of RSK2 inhibits cell proliferation and sensitizes melanoma cells to vemurafenib. Mechanistically, RSK2 enhances the phosphorylation of FOXO1 by interacting with FOXO1 and promoting its subsequent degradation, leading to upregulation of cyclin D1 in melanoma cells. These results not only reveal the presence of a RSK2-FOXO1-cyclin D1 signaling pathway in melanoma, but also provide a potential therapeutic strategy to enhance the efficacy of vemurafenib against cancer.Background: Long noncoding RNA SNHG10 has been reported to promote the development of liver cancer. While by analyzing The Cancer Genome Atlas (TCGA) dataset we observed the downregulation of SNHG10 in non-small cell lung cancer (NSCLC). This study aimed to investigate the roles of SNHG10 in NSCLC. Materials and Methods: This study included 60 pairs of NSCLC and nontumor tissue samples collected from 60 NSCLC patients (males and females, 39–66 years, 50.9 ± 5.5 years). Gene expression was detected by quantitative polymerase chain reaction and western blot. Overexpression experiments were used to analyze gene interactions. Effects of cell transfections on cell proliferation were analyzed by performing CCK-8 cell proliferation assays. Results: We confirmed the downregulation of SNHG10 in NSCLC. In addition, low expression level of SNHG10 predicted the poor survival of NSCLC patients. SNHG10 can directly interact with miR-543, while overexpression of miR-543 failed to downregulate SNHG10. However, SNHG10 overexpression led to upregulation of sirtuin 1 (SIRT1), a downstream target of miR-543. Cell proliferation assay showed that SNHG10 and SIRT1 overexpression led to the decreased proliferation rate of NSCLC cells. In contrast, miR-543 over-expression played an opposite role and reduced the effects of SNHG10 and SIRT1 overexpression. Conclusions: In conclusion, SNHG10 sponges miR-543 to upregulate tumor suppressive SIRT1 in NSCLC to suppress cell proliferation.
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Abstract Background Vemurafenib, an inhibitor of genetically activated BRAF, is now commonly prescribed for metastatic melanoma harboring a BRAF mutation. Reports on side effects have focused on cutaneous complications. We here present a case of a severe pan-uveitis associated with vemurafenib use. Case presentation A 63-year old female was treated with the BRAF inhibitor vemurafenib for metastatic melanoma. After seven weeks of treatment, she developed near-complete visual loss in the course of a few days, as a result of severe uveitis. Vemurafenib had to be discontinued and systemic and topical corticosteroids were initiated. The visual symptoms improved slowly, however the cerebral metastases progressed and the patient died from her disease. Conclusion Treatment with vemurafenib has become an important component of standard clinical care for patients with metastatic melanoma. In addition, it is one of the best examples of genotype-directed therapy. This case illustrates that vemurafenib-induced uveitis can develop fast and be slow to resolve. Awareness of this potentially severe side effect is of major importance to oncologists and aggressive treatment should be considered.
Surgical oncology
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Vemurafenib is a B-raf inhibitor which is widely used in treatment of melanoma patients with B-RAF V600E mutation. Majority of patients treated with vemurafenib develop resistance against the drug. Here, we asssessed the effectiveness of a combination drug therapy in vemurafenib resistant melanoma cells. Vemurafenib resistant A375 melanoma cells (A375Res cells) were developed by growing parental cells in increasing concentrations of the drug. The A375Res cells were 50 times more resistant (higher IC50 value), had reduced cell doubling time, were less responsive to the antiproliferative activity of Vemurafenib and showed increased tumor forming potential as compared to the parental cells. Vemurafenib inhibited phosphorylation of MEK 1/2 and ERK 1/2 at the concentrations far less than those that were effective in parental cells. Compared to the other drugs sorafenib in combination with vemurafenib significantly inhibited proliferation of A375Res cells. These findings show that Sorafenib, in combination with Vemurafenib, is a more effective method for treatment of melanoma with B-Raf 600E mutation.
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Vemurafenib, a BRAF inhibitor, is FDA-approved for the treatment of metastatic melanoma in patients who harbor the BRAF V600E mutation. By inhibiting BRAF, vemurafenib prevents the mitogen-activated protein kinase (MAPK) pathway from driving melanoma growth. Here we present a patient with paradoxical activation of the MAPK pathway by vemurafenib, ultimately resulting in deleterious cutaneous manifestations. An emphasis on close follow-up is warranted for new or changing lesions for patients on this medication and other BRAF inhibitors.
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5例の転移性悪性黒色腫に対しvemurafenibを投与した。年齢は50歳から62歳（平均56.2±4.6歳），男性3例，女性2例，病型はsuperficial spreading melanoma（SSM）が4 例，acral lentigenous melanoma（ALM）が1例であった。効果はcomplete remission（CR）1例，stable disease（SD）2例，中止2例であった。Vemurafenibによる副作用として，QTc延長，薬疹，低K血症などがみられた。 特に，多彩な副作用を呈した1例の経験から，免疫チェックポイント阻害薬投与後のvemurafenibにより重症薬疹が出現しやすいこと，およびvemurafenibとステロイド中等量以上の併用においては，易感染性となる可能性があることを念頭に投与する必要があると考えた。
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<div>Abstract<p>Acquired clinical resistance to vemurafenib, a selective BRAF<sup>V600E</sup> inhibitor, arises frequently after short-term chemotherapy. Because inhibitions of targets in the RAF–MEK–ERK pathway result in G<sub>0</sub>–G<sub>1</sub> cell-cycle arrest, vemurafenib-resistant cancer cells are expected to escape this cell-cycle arrest and progress to the subsequent G<sub>2</sub>–M phase. We hypothesized that a combined therapy using vemurafenib with a G<sub>2</sub>–M phase blocking agent will trap resistant cells and overcome vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values of our novel tubulin inhibitor ABI-274 and vemurafenib on parental human A375 and MDA-MB-435 melanoma cell lines to be 0.32 and 0.1, respectively, suggesting strong synergy for the combination. We then developed an A375RF21 subline with significant acquired resistance to vemurafenib and confirmed the strong synergistic effect. Next, we studied the potential mechanisms of overcoming vemurafenib resistance. Flow cytometry confirmed that the combination of ABI-274 and vemurafenib synergistically arrested cells in the G<sub>1</sub>–G<sub>2</sub>–M phase, and significantly increased apoptosis in both parental A375 and the vemurafenib-resistant A375RF21 cells. Western blot analysis revealed that the combination treatment effectively reduced the level of phosphorylated and total AKT, activated the apoptosis cascade, and increased cleaved caspase-3 and cleaved PARP, but had no significant influence on the level of extracellular signal–regulated kinase (ERK) phosphorylation. Finally, <i>in vivo</i> coadministration of vemurafenib with ABI-274 showed strong synergistic efficacy in the vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in patients with melanoma who inevitably become resistant to current vemurafenib therapy. <i>Mol Cancer Ther; 13(1); 16–26. ©2013 AACR</i>.</p></div>
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In patients with metastatic melanoma, standard cytotoxic drugs such as dacarbazine have no proven impact on survival. Vemurafenib is the first BRAF protein inhibitor to be approved for the treatment of melanoma. In about half of patients with melanoma, this protein, important for cell growth, is dysregulated owing to a mutation (V600) in the gene that encodes it. An unblinded clinical trial that included 675 patients with metastatic melanoma harbouring a V600 BRAF mutation compared oral vemurafenib with intravenous dacarbazine. An interim analysis showed a statistically significant increase in the median overall survival time of about 1.5 months with vemurafenib (9.2 versus 7.7 months). These results are too preliminary to determine the survival advantage, if any, conferred by vemurafenib. About 20% of patients treated with vemurafenib developed skin cancer. The most common adverse effects were skin rash (37%), photosensitivity (33%), diarrhoea (28%), and arthralgia (54%). Vemurafenib also causes ocular disorders, including uveitis, and prolongs the QT interval in a dose-dependent manner. The potential for pharmacokinetic interactions is high: vemurafenib inhibits P-glycoprotein and CYP 1A2, and induces CYP 3A4. In practice, vemurafenib should only be used in rigorous clinical trials, on a case-by-case basis.
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The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown.To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs.A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex.In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 (95% confidence interval [CI] 5.0-6.9) months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone (adjusted hazard ratio [HRa] 2.37; 95% CI 0.97-5.76), which became statistically significant in a sensitivity analysis (HRa 4.56; 95% CI 1.51-13.75).There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation.
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Abstract This study aimed to evaluate the impact of early adverse events on overall survival (OS), progression‐free survival (PFS) and objective response within a pooled secondary analysis of participants treated with first‐line vemurafenib or vemurafenib plus cobimetinib in the clinical trials BRIM3 and coBRIM. The study included 583 participants who received vemurafenib monotherapy and 247 who received vemurafenib plus cobimetinib. Adverse events requiring vemurafenib/cobimetinib dose adjustment within the first 28 days of therapy were significantly associated with OS (hazard ratio (HR) [95% CI]: dose reduced/interrupted = 0.79 [0.65–0.96]; drug withdrawn = 1.18 [0.71–1.96]; p = 0.032), PFS (HR [95% CI]: dose reduced/interrupted = 0.82 [0.67–0.99]; drug withdrawn = 1.58 [0.97–2.58]; p = 0.017) and objective response (odds ratio (OR) [95% CI]: dose reduced/interrupted = 1.35 [0.99–1.85]; drug withdrawn = 0.17 [0.06–0.43]; p = <0.001). Arthralgia occurring within the first 28 days of vemurafenib or vemurafenib plus cobimetinib therapy was also significantly associated with favourable OS ( p = 0.026), PFS ( p = 0.042) and objective response ( p = 0.047).
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Introduction: Advanced melanoma with a BRAF V600 mutation responds to treatment with BRAF inhibitors such as vemurafenib, with great improvement in tumour response and patient survival. Despite early and often dramatic responses, resistance to vemurafenib develops. Concurrent inhibition of a downstream protein, MEK, also involved in the MAPK oncogenic signalling pathway, defers development of resistance. The MEK inhibitor cobimetinib has been successfully and safely combined with vemurafenib, further improving response rate and survival when compared to vemurafenib monotherapy.Areas covered: This article covers the mechanism of action of both vemurafenib and cobimetinib, in addition to describing results from the key Phase I and Phase III studies which led to registration of the combination in the US and Europe as a therapeutic option for advanced BRAF mutant melanoma. The safety profile of these agents is also discussed in detail, including similarities with and differences from the competitor compounds dabrafenib and trametinib.Expert opinion: Vemurafenib in combination with cobimetinib provides an alternative BRAF/MEK blockade. The combination is tolerable, safe and effective and results in fewer skin toxicities than vemurafenib monotherapy.
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