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1.
Oncogene ; 35(10): 1225-35, 2016 Mar 10.
Article in English | MEDLINE | ID: mdl-26073081

ABSTRACT

The mechanisms by which some melanoma cells adapt to Serine/threonine-protein kinase B-Raf (BRAF) inhibitor therapy are incompletely understood. In the present study, we used mass spectrometry-based phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF mutant and PTEN null. Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent. These effects were recapitulated through BRAF siRNA knockdown and following treatment with chemotherapeutic drugs. Increased fibronectin expression was also observed in mouse xenograft models as well as specimens from melanoma patients undergoing BRAF inhibitor treatment. Analysis of a melanoma tissue microarray showed loss of PTEN expression to predict for a lower overall survival, with a trend for even lower survival being seen when loss of fibronectin was included in the analysis. Mechanistically, the induction of fibronectin limited the responses of these PTEN-null melanoma cell lines to vemurafenib, with enhanced cytotoxicity observed following the knockdown of either fibronectin or its receptor α5ß1 integrin. This in turn abrogated the cytotoxic response to BRAF inhibition via increased AKT signaling, which prevented the induction of cell death by maintaining the expression of the pro-survival protein Mcl-1. The protection conveyed by the induction of FN expression could be overcome through combined treatment with a BRAF and PI3K inhibitor.


Subject(s)
Fibronectins/metabolism , Melanoma/pathology , PTEN Phosphohydrolase/deficiency , PTEN Phosphohydrolase/genetics , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Animals , Cell Line, Tumor , Cell Survival/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , Humans , Integrin alpha5beta1/metabolism , Mice , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Proteomics , Proto-Oncogene Proteins B-raf/deficiency , RNA, Small Interfering/genetics , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
2.
Br J Cancer ; 112(2): 217-26, 2015 Jan 20.
Article in English | MEDLINE | ID: mdl-25180764

ABSTRACT

In recent years, melanoma has become a poster-child for the development of oncogene-directed targeted therapies. This approach, which has been exemplified by the development of small-molecule BRAF inhibitors and the BRAF/MEK inhibitor combination for BRAF-mutant melanoma, has brought new hope to patients. Despite these successes, treatment failure seems near inevitable in the majority of cases­even in individuals treated with the BRAF/MEK inhibitor doublet. In the current review, we discuss the future of combination strategies for patients with BRAF-mutant melanoma as well as the emerging therapeutic options for patients with NRAS-mutant and BRAF/NRAS-wild-type melanoma. We also outline some of the newest developments in the in-depth personalisation of therapy that should allow melanoma treatment to continue shaping the field precision cancer medicine.


Subject(s)
Proto-Oncogene Proteins B-raf/genetics , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Drug Resistance, Neoplasm/genetics , GTP Phosphohydrolases/genetics , Humans , Melanoma/drug therapy , Melanoma/genetics , Membrane Proteins/genetics , Molecular Targeted Therapy , Mutation, Missense , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics
3.
Oncogene ; 32(25): 3009-18, 2013 Jun 20.
Article in English | MEDLINE | ID: mdl-23069660

ABSTRACT

The recent years have seen a significant shift in the expectations for the therapeutic management of disseminated melanoma. The clinical success of BRAF targeted therapy suggests that long-term disease control may one day be a reality for genetically defined subgroups of melanoma patients. Despite this progress, few advances have been made in developing targeted therapeutic strategies for the 50% of patients whose melanomas are BRAF wild-type. The most well-characterized subgroup of BRAF wild-type tumors is the 15-20% of all melanomas that harbor activating NRAS (Neuroblastoma Rat Sarcoma Virus) mutations. Emerging preclinical and clinical evidence suggests that NRAS mutant melanomas have patterns of signal transduction and biological behavior that is distinct from BRAF mutant melanomas. This overview will discuss the unique clinical and prognostic behavior of NRAS mutant melanoma and will summarize the emerging data on how NRAS-driven signaling networks can be translated into novel therapeutic strategies.


Subject(s)
GTP Phosphohydrolases/genetics , Melanoma/genetics , Melanoma/therapy , Membrane Proteins/genetics , Skin Neoplasms/genetics , Skin Neoplasms/therapy , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Farnesyl-Diphosphate Farnesyltransferase/metabolism , Humans , Melanoma/metabolism , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism , Mutation , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Prognosis , Proto-Oncogene Proteins B-raf/metabolism , Signal Transduction , Skin Neoplasms/metabolism
4.
Br J Cancer ; 102(12): 1724-30, 2010 Jun 08.
Article in English | MEDLINE | ID: mdl-20531415

ABSTRACT

BACKGROUND: Resistance to BRAF inhibitors is an emerging problem in the melanoma field. Strategies to prevent and overcome resistance are urgently required. METHODS: The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot. The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture. RESULTS: BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling. Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy. A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance. CONCLUSION: Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.


Subject(s)
Drug Resistance, Neoplasm , Extracellular Signal-Regulated MAP Kinases/metabolism , Melanoma/drug therapy , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Apoptosis/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Indoles/pharmacology , MAP Kinase Signaling System , Mitogen-Activated Protein Kinases/metabolism , Mutation , Signal Transduction/drug effects , Sulfonamides/pharmacology , Time Factors
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