Dataset Information

Phosphoproteomic Analysis of Cell-Based Resistance to BRAF Inhibitor Therapy in Melanoma.

ABSTRACT: The treatment of melanoma by targeted inhibition of the mutated kinase BRAF with small molecules only temporarily suppresses metastatic disease. In the face of chemical inhibition tumor plasticity, both innate and adaptive, promotes survival through the biochemical and genetic reconfiguration of cellular pathways that can engage proliferative and migratory systems. To investigate this process, high-resolution mass spectrometry was used to characterize the phosphoproteome of this transition in vitro. A simple and accurate, label-free quantitative method was used to localize and quantitate thousands of phosphorylation events. We also correlated changes in the phosphoproteome with the proteome to more accurately determine changes in the activity of regulatory kinases determined by kinase landscape profiling. The abundance of phosphopeptides with sites that function in cytoskeletal regulation, GTP/GDP exchange, protein kinase C, IGF signaling, and melanosome maturation were highly divergent after transition to a drug resistant phenotype.

SUBMITTER: Parker R

PROVIDER: S-EPMC4432663 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Phosphoproteomic Analysis of Cell-Based Resistance to BRAF Inhibitor Therapy in Melanoma.

Parker Robert R Vella Laura J LJ Xavier Dylan D Amirkhani Ardeshir A Parker Jimmy J Cebon Jonathan J Molloy Mark P MP

Frontiers in oncology 20150515

The treatment of melanoma by targeted inhibition of the mutated kinase BRAF with small molecules only temporarily suppresses metastatic disease. In the face of chemical inhibition tumor plasticity, both innate and adaptive, promotes survival through the biochemical and genetic reconfiguration of cellular pathways that can engage proliferative and migratory systems. To investigate this process, high-resolution mass spectrometry was used to characterize the phosphoproteome of this transition in vi ...[more]

PMID: 26029660

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Project description:The toxicity spectrum between Chinese and Caucasian patients with melanoma who were treated with BRAF inhibitors (BRAFi) may differ. The purpose of the present study was to assess the safety and tolerability of BRAFi and BRAFi-based combination therapies [MEK inhibitors (MEKi) or anti-programmed death-1 (PD-1) antibody] in Chinese patients with BRAF V600E/K mutation-positive metastatic melanoma. We also investigated whether treatment-related adverse events (AEs) correlated with the prognosis. This retrospective study collected data from 43 patients with BRAF V600E/K mutation-positive metastatic melanoma from a single Chinese cancer center. Of the 43 patients, 12 patients received BRAFi monotherapy, 12 patients received BRAFi+MEKi, and 19 patients received BRAFi combined with the anti-PD-1 antibody. The median follow-up time was 19 months. In the BRAFi group, the most common AEs were rashes, palmoplantar erythrodysesthesia, and arthralgia. Four out of 12 (30%) patients experienced grade 3-4 treatment-related AEs. All grades of AEs in the BRAFi+MEKi group were similar to the BRAFi group, except for higher pyrexia (58.3%) and fewer cutaneous AEs. Three out of 12 (25%) patients experienced grade 3-4 AEs, especially pyrexia (16.7%). In the BRAFi+anti-PD-1 antibody group, AEs were similar to the BRAFi group, except for an increased aminotransferase level (36.8%), increased bilirubin (31.6%), and hypothyroidism (15.8%). Eleven out of 19 (57.9%) patients experienced grade 3-4 AEs and four out of 19 (21%) patients discontinued the therapy due to AEs. Treatment-related hepatotoxicity (trHE), defined as an increase in either alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin levels, was the only AE identified as a significant poor-prognosis indicator in this study. The median progression-free survival of patients with trHE (41.9%) was 8 months, whereas it was 18 months for those without trHE [p = 0.046, hazard ratio (HR) = 2.116]. Moreover, this association was independent of medication regimens (p = 0.014, HR = 2.971). The overall response rate of patients with trHE was significantly lower than those without trHE (44.4 vs. 60.0%, p = 0.024), and we observed a similar trend in patients treated with BRAFi, BRAFi+MEKi, and BRAFi+anti-PD-1 antibody. In conclusion, BRAFi and BRAFi-based combination therapies were tolerable with reversible AEs in Chinese patients with melanoma. The trHE in patients receiving BRAFi and BRAFi-based regimens might indicate a poor therapy-related prognosis.

Dataset Information

Phosphoproteomic Analysis of Cell-Based Resistance to BRAF Inhibitor Therapy in Melanoma.

Publications

Phosphoproteomic Analysis of Cell-Based Resistance to BRAF Inhibitor Therapy in Melanoma.

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