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.
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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.
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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.
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Project description:Acquired resistance to combination dabrafenib/trametinib therapy in BRAF mutant metastatic melanoma
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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.
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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.
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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.
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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. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAFand MEK1/2 in PTEN null, BRAFV600E cells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with inhibitors for mutant BRAF/MEK1/2 identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600E cells. The findings indicate PTEN null BRAFV600E melanoma becomes dependent on ERBB/HER signaling when treated with clinically approved BRAF and MEK inhibitors. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.
2024-04-23 | PXD033866 | Pride
Project description:Approximately half of BRAF-mutated Non-small cell lung cancers (NSCLCs) harbor a non-V600 BRAF mutation, accounting for ?40,000 annual deaths worldwide. Recent studies have revealed the benefits of combined targeted therapy with a RAF-inhibitor (Dabrafenib) and a MEK-inhibitor (Trametinib) in treating V600 BRAF mutant cancers, including NSCLC. In contrast, sensitivity of non-V600 BRAF mutations to these inhibitors is not documented. Non-V600 mutations can either increase or impair BRAF kinase activity. However, impaired BRAF kinases can still activate the ERK pathway in a CRAF-dependent manner. Herein, beyond describing a cohort of BRAF mutant NSCLC patients and functionally analyzing 13 tumor-derived BRAF mutations, we demonstrate that both types of non-V600 BRAF mutations can be sensitive to clinically relevant doses of Dabrafenib and Trametinib in HEK293T cells, in lung epithelial cellular model (BEAS-2B) and in human cancer cell lines harboring non-V600 BRAF mutations. ERK activity induced by both types of these mutations is further reduced by combinatorial drug treatment. Moreover, the combination leads to more prolonged ERK inhibition and has anti-proliferative and pro-apoptotic effects in cells harboring both types of non-V600 BRAF mutations. This study provides a basis for the clinical exploration of non-V600 BRAF mutant lung cancers upon treatment with Trametinib and Dabrafenib.
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