B-Raf inhibition in conjunctival melanoma cell lines with PLX 4720

Riechardt, Aline I.; Maier, Anna-Karina B.; Nonnenmacher, Anika; Reichhart, Nadine; Keilholz, Ulrich; Kociok, Norbert; Strauß, Olaf; Joussen, Antonia M.; Gundlach, Enken

doi:10.1136/bjophthalmol-2015-306689

Cited by 14 publications

(13 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although JQ1 has not yet been tested as a targeted clinical agent in UM, this BETi exhibits very broad anticancer effects and has previously demonstrated inhibition of tumour growth in an animal model (Ambrosini et al, 2015), consistent with high levels of transcriptional repression revealed in our UM study (Figures 3 and 5). We extend these published findings by demonstrating that CoM cell models also exhibit sub-micromolar sensitivity to JQ1, despite GNAQ/11-wt status and the presence of a BRAF mutation in CRMM1, which sensitizes these cells to the V600E-selective BRAF inhibitors PLX4720 (Riechardt et al, 2015) and vemurafenib (PLX4032) (Figure 6a). When enrichment for mRNAs in specific canonical pathways and their associated cellular functions were analysed, the likely functional consequences on cell survival and proliferative mechanisms through kinome reprogramming by JQ1 in UM and CoM cells became apparent ( Figure 3b).…”

Section: Discussionsupporting

confidence: 79%

Kinome‐wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics

Bailey

Clarke

Kalirai

et al. 2017

Pigment Cell Melanoma Res

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 79%

Kinome‐wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics

Bailey

Clarke

Kalirai

et al. 2017

Pigment Cell Melanoma Res

View full text Add to dashboard Cite

show abstract

“…; Riechardt et al. ). Unfortunately, many cutaneous melanoma patients treated with a BRAF inhibitor develop resistance, causing reactivation of the MAPK pathway (Hertzman & Egyhazi ).…”

Section: Discussionmentioning

confidence: 99%

“…BRAF inhibitors have recently been investigated in BRAF ‐mutated CM cell lines, showing promising effects of reduced CM proliferation rates (Riechardt et al. ). Apart from BRAF inhibitors being potentially useful for the treatment of advanced CM, BRAF inhibition was found to be efficient as an adjuvant treatment in a case of extensive CM without metastasis (Pahlitzsch et al.…”

Section: Discussionmentioning

confidence: 99%

Conjunctival malignant melanoma in Denmark: epidemiology, treatment and prognosis with special emphasis on tumorigenesis and genetic profile

Larsen

2016

Acta Ophthalmologica

View full text Add to dashboard Cite

Conjunctival malignant melanoma is a rare disease associated with considerable mortality. Most published data have been based on case reports or series of referred patients. In addition, very little is known about the genetic and epigenetic profile of conjunctival melanoma and the resemblance to uveal, cutaneous and mucosal melanoma. The aim was to determine the incidence rate of conjunctival melanoma, and to relate clinicopathological features and treatment to prognosis. A further aim was to determine the prevalence of BRAF mutations in conjunctival melanoma, to determine whether BRAF mutations are early events in pathogenesis, and relate clinicopathological features and prognosis to BRAF‐mutation status. Finally, we wanted to identify tumour‐specific and prognostic microRNAs in conjunctival melanoma, and to compare these with the microRNA expression of other melanoma subtypes. In order to investigate these rare tumours, we studied all the conjunctival melanomas that had been surgically removed in Denmark over a period of 52 years (1960–2012). Tissue samples, clinical files, pathology reports and follow‐up data were collected and re‐evaluated. Using droplet digital polymerase chain reaction and immunohistochemistry, we investigated BRAF mutations; and using microRNA expression profiling, we investigated differentially expressed microRNAs. The overall incidence of conjunctival melanoma was 0.5/1 000 000/year, and it increased in Denmark over 52 years. The increase was mainly caused by an increase in older patients (>65 years) and bulbar lesions. Clinicopathological features significantly associated with a poor prognosis were extrabulbar location, involvement of adjacent tissue structures, tumour thickness exceeding 2 mm and local tumour recurrence. Patients undergoing incisional biopsy and/or treatment involving excision without adjuvant therapy fared worse than patients treated with excision and any type of adjuvant treatment. We found that 35% (39/110) of conjunctival melanomas were BRAF‐mutated, and the incidence of BRAF mutations was constant over time. BRAF‐mutation status corresponded in conjunctival melanoma and paired premalignant lesions. BRAF mutations were more frequent in males, in young patients, and in tumours with a sun‐exposed tumour location (bulbar conjunctiva or caruncle), with a mixed or non‐pigmented colour, with absence of primary acquired melanosis, and with origin in a nevus. Immunohistochemistry was able to accurately detect BRAF V600E mutations. In univariate analysis, distant metastatic disease was associated with BRAF mutations. No prognostic associations with BRAF mutations were identified in multivariate analyses. MicroRNA expression analysis revealed 25 tumour‐specific microRNAs in conjunctival melanoma. Five possibly oncogenic miRNAs (miR‐20b‐5p, miR‐146b‐5p, miR‐146a‐5p, miR‐506‐3p and miR‐509‐3p) were up‐regulated. Seven microRNAs (miR‐30d‐5p, miR‐138‐5p, miR‐146a‐5p, miR‐500a‐5p, miR‐501‐3p, miR‐501‐5p and miR‐502‐3p) were significantly and simultaneously up‐regulated i...

show abstract

“…24 The efficiency of direct BRAF inhibition in conjunctival melanoma (CJM) has been evaluated in vitro in two studies. 25,26 The response to BRAF inhibition in advanced metastatic CJM has been variable, ranging from a partial response lasting 1 month 27 to significant tumor regression peaking after 4.5 months. 28 A complete regression for 38 months of an irradiated metastatic CJM treated with vemurafenib has also been documented.…”

mentioning

confidence: 99%

Conjunctival Melanoma Targeted Therapy: MAPK and PI3K/mTOR Pathways Inhibition

Zaoui

Bucher

Rimoldi

et al. 2019

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PURPOSE. To analyze the activity of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases/mechanistic target of rapamycin (PI3K/mTOR) pathways in benign and malignant conjunctival melanocytic proliferations and explore whether specific inhibitors can suppress growth of conjunctival melanoma (CJM) cells. METHODS. The presence of a BRAF V600E mutation and activation of ERK, MEK, S6, and AKT were assessed with immunohistochemistry in 35 conjunctival nevi and 31 melanomas. Three CJM cell lines were used: CRMM1, carrying the BRAF V600E mutation; CRMM2, harboring the NRAS Q61L mutation; and T1527A, with a BRAF G466E mutation. WST-1 assays were performed with a BRAF inhibitor (vemurafenib), two MEK inhibitors (trametinib, selumetinib), a PI3K inhibitor (pictilisib), and a dual PI3K/mTOR inhibitor (dactolisib). The phosphorylation of ERK, MEK, and S6 were tested with western blots and apoptosis with cleaved caspase-3 immunostaining. RESULTS. A BRAF V600E mutation was detected in 42.6% of nevi and in 35.5% of CJM. MEK and ERK activation were higher in CJM, occurring in 62.9% and 45.7% of the nevi and 90.3% and 96.8% of the CJM, respectively. There was also a significant increase in S6 activation in CJM (90.3%) compared with the nevi (20%). CRMM1 was sensitive to trametinib and the PI3K inhibitors but only marginally to vemurafenib. CRMM2 was moderately sensitive to pictilisib, whereas T1527A was resistant to all drugs tested. CONCLUSIONS. The MAPK pathway activity in CJM is increased, not only as a consequence of the BRAF V600E mutation. Targeted therapy may be useful for patients with CJM, especially those with activating BRAF mutations, whereas NRAS-mutated melanomas are relatively resistant.

show abstract

B-Raf inhibition in conjunctival melanoma cell lines with PLX 4720

Abstract: Proliferation inhibition of conjunctival melanoma cells by PLX 4720 depends on their B-Raf genotype. Therefore, therapeutic application of B-Raf inhibitors should take into account the specific B-Raf genotype.

Cited by 14 publications

References 24 publications

Kinome‐wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics

Kinome‐wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics

Conjunctival malignant melanoma in Denmark: epidemiology, treatment and prognosis with special emphasis on tumorigenesis and genetic profile

Conjunctival Melanoma Targeted Therapy: MAPK and PI3K/mTOR Pathways Inhibition

Contact Info

Product

Resources

About