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Phosphoproteomic analysis of basal and therapy-induced adaptive signaling networks in BRAF and NRAS mutant melanoma.

ABSTRACT: Basal and kinase inhibitor driven adaptive signaling has been examined in a panel of melanoma cell lines using phosphoproteomics in conjunction with pathway analysis. A considerable divergence in the spectrum of tyrosine-phosphorylated peptides was noted at the cell line level. The unification of genotype-specific cell line data revealed the enrichment for the tyrosine-phosphorylated cytoskeletal proteins to be associated with the presence of a BRAF mutation and oncogenic NRAS to be associated with increased receptor tyrosine kinase phosphorylation. A number of proteins including cell cycle regulators (cyclin dependent kinase 1, cyclin dependent kinase 2, and cyclin dependent kinase 3), MAPK pathway components (Extracellular signal regulated kinase 1 and Extracellular signal regulated kinase 2), interferon regulators (tyrosine kinase-2), GTPase regulators (Ras-Rasb interactor 1), and controllers of protein tyrosine phosphorylation (dual specificity tyrosine (Y) phosphorylation regulated kinase 1A and protein tyrosine phosphatase receptor type A) were common to all genotypes. Treatment of a BRAF-mutant/phosphatase and tensin homologue (PTEN) null melanoma cell line with vemurafenib led to decreased phosphorylation of ERK, phospholipase C1, and ?-catenin with increases in receptor tyrosine kinase phosphorylation, signal transduction and activator of signaling 3, and glycogen synthase kinase 3? noted. In NRAS-mutant melanoma, MEK inhibition led to increased phosphorylation of epidermal growth factor receptor signaling pathway components, Src family kinases, and protein kinase C? with decreased phosphorylation seen in STAT3 and ERK1/2. Together these data present the first systems level view of adaptive and basal phosphotyrosine signaling in BRAF- and NRAS-mutant melanoma.

SUBMITTER: Fedorenko IV

PROVIDER: S-EPMC4389901 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Phosphoproteomic analysis of basal and therapy-induced adaptive signaling networks in BRAF and NRAS mutant melanoma.

Fedorenko Inna V IV Fang Bin B Munko Ana Cecelia AC Gibney Geoffrey T GT Koomen John M JM Smalley Keiran S M KS Smalley Keiran S M KS

Proteomics 20141217 2-3

Basal and kinase inhibitor driven adaptive signaling has been examined in a panel of melanoma cell lines using phosphoproteomics in conjunction with pathway analysis. A considerable divergence in the spectrum of tyrosine-phosphorylated peptides was noted at the cell line level. The unification of genotype-specific cell line data revealed the enrichment for the tyrosine-phosphorylated cytoskeletal proteins to be associated with the presence of a BRAF mutation and oncogenic NRAS to be associated w ...[more]

PMID: 25339196

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Project description:Simple Summary Targeted radionuclide therapy (TRT) aims to selectively deliver radioactive molecules to tumor cells. For this purpose, we deliver iodine-131 ([131I]) to melanoma cells by using our laboratory-developed melanin specific radiotracer, the ICF01012. Approximately 50% and 20%–30% of human melanomas have activating mutation in BRAF or NRAS genes, respectively. These mutations lead to a constitutive activation of the MAPK/ERK pathway, which is known to be involved in tumor cells’ radioresistance. In this work, we showed using 3D in vitro tumor models, an additive efficiency of combining [131I]ICF01012-TRT and MAPK/ERK inhibitors in BRAF- and NRAS-mutant melanoma cells. In mice bearing NRASQ61K-mutated melanoma, TRT induced an impressive decrease in tumor growth, as well as a highly extended survival. Additionally, we showed that TRT reduces the metastatic capacity of melanoma, especially through lymph-node dissemination. These results are therefore of great interest, especially for patients with NRAS-mutant metastatic melanoma who currently lack specific efficient therapies. Abstract Purpose: To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance. Methods: For TRT, we used a melanin radiotracer ([131I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAFV600E SK-MEL-3, murine NRASQ61K 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRASQ61K 1007 syngeneic model. Results: TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. In mice bearing NRASQ61K 1007 melanoma, [131I]ICF01012 induced a significant extended survival (92 vs. 44 days, p < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation. Conclusion: Our data suggest that [131I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [131I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.

Dataset Information

Phosphoproteomic analysis of basal and therapy-induced adaptive signaling networks in BRAF and NRAS mutant melanoma.

Publications

Phosphoproteomic analysis of basal and therapy-induced adaptive signaling networks in BRAF and NRAS mutant melanoma.

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