Systemic therapy of metastatic melanoma

Rauschenberg, Ricarda; Garzarolli, Marlene; Dietrich, U.; Beissert, Stefan; Meier, Friedegund

doi:10.1111/ddg.12891

Cited by 18 publications

(16 citation statements)

References 63 publications

(114 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Additionally, grade 3/4 events and the discontinuation rate due to adverse events are also lower in the combination compared to the monotherapy. Numerous clinical trials and real-world experience confirm that combinations of BRAFi (dabrafenib, vemurafenib, encorafenib) with MEKi (trametinib, cobimetinib, binimetinib) have a favourable safety profile and are generally well tolerated in the long run (37–39). …”

Section: Discussionmentioning

confidence: 99%

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Niessner¹,

Sinnberg²,

Kosnopfel³

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its pro-apoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected. Experimental design and results BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer, spheroids, organotypic and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced an ER stress response via the PERK pathway, as detected by phosphorylation of eIF2α and upregulation of the ER stress-related factors ATF4, CHOP and NUPR1 and the pro-apoptotic protein PUMA. MEKi such as binimetinib induced the expression of the pro-apoptotic protein BIM and activation of the mitochondrial pathway of apoptosis, the latter of which was enhanced by combination with encorafenib. The increased apoptotic rates caused by the combination treatment were significantly reduced through siRNA knockdown of ATF4 and BIM, confirming its critical roles in this process. Conclusion The data presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma.

show abstract

Section: Discussionmentioning

confidence: 99%

BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma

Niessner¹,

Sinnberg²,

Kosnopfel³

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…The interaction between the PD-1 receptor and its ligands PD-L1 (B7-H1) results in T-cell inhibition and creates an immune-suppressive tumour microenvironment. PD-1 antibodies disrupt this interaction to allow the antitumour activities from T cells 2. Our case report demonstrates that PD-1 antibodies can still be effective in dialysis-dependent ESRD.…”

Section: Discussionmentioning

confidence: 77%

“…Dacarbazine is associated with an objective response rate between 5% and 14% 2. Similarly, combination chemotherapy regimens have failed to show survival benefit when compared to dacarbazine 3.…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of pembrolizumab in a patient with advanced melanoma on haemodialysis

Chang

Shirai²

2016

BMJ Case Reports

View full text Add to dashboard Cite

Patients with end-stage renal disease present with a distinct challenge in oncology. Many anticancer drugs and their metabolites are excreted by the kidney, but data to guide dose and schedule adjustments in renal dialysis are scant. Pembrolizumab is an anti-programmed cell death protein 1 monoclonal antibody proven to be effective in patients with metastatic melanoma. It has demonstrated promising results and was granted US Food and Drug Administration (FDA) approval in September, 2014 for metastatic melanoma. It was additionally approved for patients with metastatic non-small cell lung cancer by the FDA in October, 2015. We present the first case, to the best of our knowledge, of a patient with metastatic melanoma successfully treated with pembrolizumab while on haemodialysis.

show abstract

“…Combined therapy of advanced melanoma with BRAF/MEK inhibitors leads to an improvement of overall survival [1][2][3][4][5][6]. In 2014, the combined HCV-NS5A/nucleotide polymerase inhibitor Harvoni ® was approved for the treatment of chronic hepatitis C and demonstrated to be highly effective in previously untreated patients [7].…”

Section: Dear Editorsmentioning

confidence: 99%