Endothelin-1 expression and Akt activation are involved in acquired resistance to dabrafenib/trametinib combination therapy of melanoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE89090 | GEO | 2018/10/31
REPOSITORIES: GEO
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Project description:RATIONALE:BRAF and MEK inhibitors (BRAF/MEKi) are targeted therapy for proto-oncogene BRAF mutated metastatic unresectable melanoma. Compared to monotherapy, an increased cardiovascular toxicity is reported with the combination of Dabrafenib and Trametinib. This case report documents Grade 4 cardiac treatment emergent adverse effect of pericardial effusion and cardiac tamponade induced by this combination therapy. PATIENT CONCERNS:A 52 year old man presented with clinical stage II unresectable melanoma with BRAF mutation, was initiated on treatement with Dabrafenib and Trametinib. He complained of generalised edema and increased his weight by 27 kg. This progressed to shortness of breath and he underwent echocardiogram which revealed cardiac tamponade. DIAGNOSES:Emergent pericardiocentesis was performed. No definited pathology was demonstrated in laboratory analysis of pericardial fluid. Re- initiating treatment resulted in cardiac tamponade and pericardiotomy was performed by video-assisted thoracic surgical (VATS). Pericardial biopsy revealed nonspecific chronic inflammation. INTERVENTIONS:Discontinuation of treatment with Dabrafenib and Trametinib and diuretics resolved peripheral edema. Cardiac function normalized after pericardiocentesis and pericardiotomy. OUTCOMES:Treatment with Dabrafenib and Trametinib caused significant peripheral edema and pericardial effusion resulting in cardiac tamponade. Naranjo score suggests probable association of treatment induced pericardial effusion and cardiac tamponade. LESSONS:This is the first documented report of pericardial effusion and cardiac tamponade induced by Dabrafenib and Trametinib. Cardiac toxicity of BRAF/MEK inhibitors is rare but clinicans must monitor for treatment emergent adverse effects.
| S-EPMC6221704 | biostudies-literature
Project description:To report a case of uveitis and neuroretinal detachment in a patient treated with Trametinib and Dabrafenib due to metastatic cutaneous melanoma stage IV.We evaluated slit lamp examination, fundoscopy, optical coherence tomography, fluorescein and indocyanine green angiography in a 66 years old man suffering visual loss. Fundoscopy showed serous neuroretinal detachment of the fovea accompanied with white spots surrounding the fovea in both eyes. Although therapy with Trametinib and Dabrafenib was stopped uveitis anterior was seen 2 weeks later. After a year, the therapy was started again and the serous neuroretinal detachment appeared once more, however without inflammatory reaction of the anterior chamber.Patients treated with Trametinib and Dabrafenib should undergo consecutive eye examinations from the beginning of the therapy.
| S-EPMC5561643 | biostudies-other
Project description:Development of selective inhibitors of BRAF has improved the survival of patients with BRAF-mutant melanoma. The progression-free survival after treatment with a BRAF inhibitor is modest, however, and BRAF inhibitors induce cutaneous toxicity, likely due to paradoxical activation of the mitogen-activated protein kinase pathway. Combining selective BRAF and MEK inhibition, such as the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, has been shown to improve the response rate and progression-free survival in patients with advanced melanoma while significantly alleviating the paradoxical activation of mitogen-activated protein kinase. This combination treatment results in a reduction in skin toxicity relative to that seen with a BRAF inhibitor alone; however, addition of the MEK inhibitor adds other toxicities, such as pyrexia and gastrointestinal or ocular toxicity. While combined BRAF-MEK inhibition appears primed to become a standard molecular approach for BRAF-mutant melanoma, the utility of the combination has to be considered in the rapidly changing landscape of immunotherapeutics, such as immune checkpoint blockade using anti-cytotoxic T lymphocyte antigen-4 and anti-programmed death-1/programmed death-L1 antibodies. Here we review the development of the dabrafenib plus trametinib combination, the characteristics of each drug and the combination, and the role of this combination in the management of patients with BRAF-mutant melanoma.
| S-EPMC4075957 | biostudies-literature
Project description:Acquired resistance to combination dabrafenib/trametinib therapy in BRAF mutant metastatic melanoma
| PRJEB7503 | ENA
Project description:Langerhans cell histiocytosis (LCH) is a rare, heterogenous, neoplastic disorder primarily affecting children. BRAF mutations have been reported in >50% of patients with LCH. The selective BRAF inhibitor, dabrafenib, in combination with the MEK1/2 inhibitor, trametinib, has been approved in select BRAF V600-mutant solid tumors. Two open-label phase 1/2 studies were conducted in pediatric patients with BRAF V600-mutant, recurrent/refractory malignancies treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772). The primary objectives of both studies were to determine safe and tolerable doses that achieve similar exposure to the approved doses for adults. Secondary objectives included safety, tolerability, and preliminary antitumor activity. Thirteen and 12 patients with BRAF V600-mutant LCH received dabrafenib monotherapy and in combination with trametinib, respectively. Investigator-assessed objective response rates per Histiocyte Society criteria were 76.9% (95% confidence interval [CI], 46.2-95.0) and 58.3% (95% CI, 27.7-84.8) in the monotherapy and combination studies, respectively. More than 90% of responses were ongoing at study completion. The most common treatment-related adverse events (AEs) were vomiting and increased blood creatinine with monotherapy and pyrexia, diarrhea, dry skin, decreased neutrophil count, and vomiting with combination therapy. Two patients each discontinued treatment with monotherapy and combination therapy because of AEs. Overall, dabrafenib monotherapy or in combination with trametinib demonstrated clinical efficacy and manageable toxicity in relapsed/refractory BRAF V600-mutant pediatric LCH, with most responses ongoing. Safety was consistent with that reported in other pediatric and adult conditions treated with dabrafenib plus trametinib.
| S-EPMC10393756 | biostudies-literature
Project description:BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib.
| S-EPMC6004887 | biostudies-literature
Project description:BackgroundCombination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines.MethodsCancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones.ResultsTwenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1 months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer.ConclusionsHSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.
| S-EPMC10793106 | biostudies-literature
Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN in the A375 melanoma cell line that harbors a BRAFV600E mutation. Kinome profiling was performed using the parental line and two PTEN KO clones (5 and 11), treated with DMSO, or treated with 100nM dabrafenib and 10nM trametinib for 1 day or for 7 days. PTEN KO cells showed dramatically increased binding of HER3 and AKT3 compared to wild type. The activation of the SOX10-FOXD3-HER3-AKT axis in PTEN KO cells could be targeted with the ERBB/HER inhibitor neratinib.
2024-04-23 | PXD033921 | Pride
Project description:Molecular sequencing after highly potent targeted gene inhibitors have suggested resistant tumors can display substantial heterogeneity. Among these various mechanisms of resistance, secondary mutations on targetable oncogenes have been identified. BRAF V600E, as a bypass mechanism on disease progression while receiving osimertinib therapy, has been reported in 3% of EGFR-mutated patients. Few case reports described the efficacy of the association of osimertinib and dabrafenib plus trametinib. Here, we report, for the first time, a case of a patient treated with this association, with a prolonged response on leptomeningeal metastasis. We also provide a comprehensive overview of the available literature on the efficacy and tolerance of this association.
| S-EPMC8474423 | biostudies-literature
Project description:Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAF(V600E) kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAF(V600E)-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor.
| S-EPMC3701070 | biostudies-literature