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• W2941397143 abstract "Recent advances in the treatment of melanoma that involve immunotherapy and B-Raf inhibition have revolutionised cancer care for this disease. However, an un-met clinical need remains in B-Raf inhibitor resistant patients where first-generation B-Raf inhibitors provide only short-term disease control. In these cases, B-Raf inhibition leads to paradoxical activation of the C-Raf – MEK – ERK signalling pathway, followed by metastasis. PDE8A has been shown to directly interact with and modulate the cAMP microdomain in the vicinity of C-Raf. This interaction promotes C-Raf activation by attenuating the PKA-mediated inhibitory phosphorylation of the kinase. We have used a novel cell-penetrating peptide agent (PPL-008) that inhibits the PDE8A – C-Raf complex in a human malignant MM415 melanoma cell line and MM415 melanoma xenograft mouse model to investigate ERK MAP kinase signalling. We have demonstrated that the PDE8A – C-Raf complex disruptor PPL-008 increased inhibitory C-Raf-S259 phosphorylation and significantly reduced phospho-ERK signalling. We have also discovered that the ability of PPL-008 to dampen ERK signalling can be used to counter B-Raf inhibitor-driven paradoxical activation of phospho-ERK in MM415 cells treated with PLX4032 (Vemurafenib). PPL-008 treatment also significantly retarded the growth of these cells. When applied to a MM415 melanoma xenograft mouse model, PPL-008C penetrated tumour tissue and significantly reduced phospho-ERK signalling in that domain. Our data suggests that the PDE8A-C-Raf complex is a promising therapeutic treatment for B-Raf inhibitor resistant melanoma." @default.
• W2941397143 created "2019-05-03" @default.
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• W2941397143 date "2019-03-25" @default.
• W2941397143 modified "2023-10-03" @default.
• W2941397143 title "Targeting B-Raf inhibitor resistant melanoma with novel cell penetrating peptide disrupters of PDE8A – C-Raf" @default.
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• W2941397143 doi "https://doi.org/10.1186/s12885-019-5489-4" @default.
• W2941397143 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6434832" @default.
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