Vemurafenib for BRAF V600 mutated advanced melanoma: Results of treatment beyond progression

Scholtens, Asbjørn M.; Foppen, Marnix H Geukes; Blank, Christian U.; Thienen, J.V. van; Haanen, John B.A.G.

doi:10.1016/j.ejca.2015.01.009

Cited by 32 publications

(20 citation statements)

References 40 publications

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“…In the clinical setting, melanoma patients developing resistance to BRAFi frequently continue treatment beyond progression. Indeed, it has been demonstrated that prolonging BRAFi therapy beyond RECIST disease progression can provide a clinical benefit [ 50 , 51 ]. Our findings suggest that targeting PTTG1 in combination with dabrafenib therapy could provide a better disease control, being the impairment of PTTG1 expression able to reduce cell proliferation, restrain the highly invasive behavior associated with acquired resistance to dabrafenib and to counteract possible stimulating effects of the drug on melanoma cell metastatic potential.…”

Section: Discussionmentioning

confidence: 99%

Targeting the PTTG1 oncogene impairs proliferation and invasiveness of melanoma cells sensitive or with acquired resistance to the BRAF inhibitor dabrafenib

et al. 2017

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The pituitary tumor transforming gene 1 (PTTG1) is implicated in tumor growth, metastasis and drug resistance. Here, we investigated the involvement of PTTG1 in melanoma cell proliferation, invasiveness and response to the BRAF inhibitor (BRAFi) dabrafenib. We also preliminary assessed the potential value of circulating PTTG1 protein to monitor melanoma patient response to BRAFi or to dabrafenib plus trametinib. Dabrafenib-resistant cell lines (A375R and SK-Mel28R) were more invasive than their drug-sensitive counterparts (A375 and SK-Mel28), but expressed comparable PTTG1 levels. Dabrafenib abrogated PTTG1 expression and impaired invasion of the extracellular matrix (ECM) in A375 and SK-Mel28 cells. In contrast, it affected neither PTTG1 expression in A375R and SK-Mel28R cells, nor ECM invasion in the latter cells, while further stimulated A375R cell invasiveness. Assessment of proliferation and ECM invasion in control and PTTG1-silenced A375 and SK-Mel28 cells, exposed or not to dabrafenib, demonstrated that the inhibitory effects of this drug were, at least in part, dependent on its ability to down-regulate PTTG1 expression. PTTG1-silencing also impaired proliferation and invasiveness of A375R and SK-Mel28R cells, and counteracted dabrafenib-induced stimulation of ECM invasion in A375R cells. Further experiments performed in A375R cells indicated that PTTG1-silencing impaired cell invasiveness through inhibition of MMP-9 and that PTTG1 expression and ECM invasion could be also reduced by the CDK4/6 inhibitor LEE011. PTTG1 targeting might, therefore, represent a useful strategy to impair proliferation and metastasis of melanomas resistant to BRAFi. Circulating PTTG1 also appeared to deserve further investigation as biomarker to monitor patient response to targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Targeting the PTTG1 oncogene impairs proliferation and invasiveness of melanoma cells sensitive or with acquired resistance to the BRAF inhibitor dabrafenib

et al. 2017

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“…Conversely, in patients who did not continue vemurafenib after progression, median OS was 11.0 from initiation of vemurafenib and 3.4 months after PD [ 14 ]. Similarly, treatment beyond progression was associated with better OS in a retrospective analysis conducted by Chan and colleagues [ 15 ] on a series of patients treated with BRAF inhibitors vemurafenib and dabrafenib as single agents in phase I/II/III/IV trials and in another retrospective analysis by Scholtens and colleagues [ 16 ].…”

Section: Introductionmentioning

confidence: 94%

Combined vemurafenib and fotemustine in patients with BRAF V600 melanoma progressing on vemurafenib

et al. 2016

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BackgroundBRAF inhibitor vemurafenib achieves high response rate and an improvement in survival in patients with BRAF-mutated metastatic melanoma. However, median progression-free survival is only 6.9 months in the phase 3 study. Retrospective analyses suggest that treatment with BRAF inhibitors beyond initial progression might be associated with improved overall survival. We aimed to prospectively investigate the activity of prolonged treatment with vemurafenib and the addition of fotemustine in patients with systemic progression on prior single-agent BRAF inhibitor.Patients and MethodsIn this two-centres, single-arm Phase 2 trial, we enrolled patients with systemic progressive disease during single-agent vemurafenib treatment. Participants received vemurafenib 960 mg twice daily or dose administered at time of disease progression with vemurafenib previous treatment and fotemustine 100 mg/m2 intravenously every three weeks. The primary endpoint was PFS.ResultsThirty-one patients were enrolled in the study; 16 patients had brain metastases at baseline. Median PFS was 3.9 months and 19 patients (61.3%) achieved disease control (1 CR, 4 PR, 14 SD). For patients achieving disease control, median duration of treatment was 6 months. Median OS was 5.8 months from enrolment and 15.4 months from start of previous vemurafenib. Five patients (16.1%) had a G3-4 AE, the most common being thrombocytopenia, which occurred in 3 patients.This trial is registered with ClinicalTrials.gov number NCT01983124.ConclusionThe combination of vemurafenib plus fotemustine has clinical activity and an acceptable safety profile in BRAF-refractory patients.

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“…BRAF inhibitors are based on the fact that 50% of melanoma tumors harbor BRAF V600 mutations, which cause increased activation of MAP kinase signaling pathway that results in melanoma cell proliferation. 6 Inhibitors of BRAF V600 mutated melanoma, such as vemurafenib and dabrafenib, increase progression-free survival and overall survival 1 , 7 , 8 , but unfortunately the resistance mechanisms usually appear to re-establish the signaling pathway and the disease progresses in the matter of months after the start of treatment. 9 …”

Section: Introductionmentioning

confidence: 99%

Electrochemotherapy with bleomycin is effective in BRAF mutated melanoma cells and interacts with BRAF inhibitors

Dolinšek

Prosen

Čemažar

et al. 2016

Radiology and Oncology

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BackgroundThe aim of the study was to explore the effectiveness of electrochemotherapy (ECT) during the treatment of melanoma patients with BRAF inhibitors. Its effectiveness was tested on BRAF mutated and non-mutated melanoma cells in vitro and in combination with BRAF inhibitors.Materials and methodsECT with bleomycin was performed on two human melanoma cell lines, with (SK-MEL-28) or without (CHL-1) BRAF V600E mutation. Cell survival was determined using clonogenic assay to determine the effectiveness of ECT in melanoma cells of different mutation status. Furthermore, the effectiveness of ECT in concomitant treatment with BRAF inhibitor vemurafenib was also determined in BRAF mutated cells SK-MEL-28 with clonogenic assay.ResultsThe survival of BRAF V600E mutated melanoma cells was even lower than non-mutated cells, indicating that ECT is effective regardless of the mutational status of melanoma cells. Furthermore, the synergistic interaction between vemurafenib and ECT with bleomycin was demonstrated in the BRAF V600E mutated melanoma cells.ConclusionsThe effectiveness of ECT in BRAF mutated melanoma cells as well as potentiation of its effectiveness during the treatment with vemurafenib in vitro implies on clinical applicability of ECT in melanoma patients with BRAF mutation and/or during the treatment with BRAF inhibitors.

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Vemurafenib for BRAF V600 mutated advanced melanoma: Results of treatment beyond progression

Cited by 32 publications

References 40 publications

Targeting the PTTG1 oncogene impairs proliferation and invasiveness of melanoma cells sensitive or with acquired resistance to the BRAF inhibitor dabrafenib

Targeting the PTTG1 oncogene impairs proliferation and invasiveness of melanoma cells sensitive or with acquired resistance to the BRAF inhibitor dabrafenib

Combined vemurafenib and fotemustine in patients with BRAF V600 melanoma progressing on vemurafenib

Electrochemotherapy with bleomycin is effective in BRAF mutated melanoma cells and interacts with BRAF inhibitors

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