Targeting B-Raf inhibitor resistant melanoma with novel cell penetrating peptide disrupters of PDE8A - C-Raf.
BMC Cancer
; 19(1): 266, 2019 Mar 25.
Article
in En
| MEDLINE
| ID: mdl-30909892
ABSTRACT
BACKGROUND:
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.METHODS:
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.RESULTS:
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.CONCLUSION:
Our data suggests that the PDE8A-C-Raf complex is a promising therapeutic treatment for B-Raf inhibitor resistant melanoma.Key words
Full text:
1
Database:
MEDLINE
Main subject:
3',5'-Cyclic-AMP Phosphodiesterases
/
Drug Resistance, Neoplasm
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Proto-Oncogene Proteins c-raf
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Cell-Penetrating Peptides
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Melanoma
Limits:
Animals
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Female
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Humans
Language:
En
Journal:
BMC Cancer
Journal subject:
NEOPLASIAS
Year:
2019
Type:
Article
Affiliation country:
United kingdom