Blair, C. M., Walsh, N., Littman, B. H., Marcoux, F. W. and Baillie, G. S. (2019) Targeting B-Raf inhibitor resistant melanoma with novel cell penetrating peptide disrupters of PDE8A – C-Raf. BMC Cancer, 19, 266. (doi: 10.1186/s12885-019-5489-4) (PMID:30909892) (PMCID:PMC6434832)
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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.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Blair, Dr Connor and Baillie, Professor George and Walsh, Nicola |
Authors: | Blair, C. M., Walsh, N., Littman, B. H., Marcoux, F. W., and Baillie, G. S. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | BMC Cancer |
Publisher: | BioMed Central |
ISSN: | 1471-2407 |
ISSN (Online): | 1471-2407 |
Published Online: | 25 March 2019 |
Copyright Holders: | Copyright © 2019 The Authors |
First Published: | First published in BMC Cancer 19:266 |
Publisher Policy: | Reproduced under a Creative Commons license |
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