Cooke, S. F. et al. (2024) Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC. Scientific Reports, 14, 8998. (doi: 10.1038/s41598-024-59451-3) (PMID:38637546)
![[img]](https://eprints.gla.ac.uk/style/images/fileicons/text.png) |
Text
324599.pdf - Published Version Available under License Creative Commons Attribution. 3MB |
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is considered the third leading cause of cancer mortality in the western world, offering advanced stage patients with few viable treatment options. Consequently, there remains an urgent unmet need to develop novel therapeutic strategies that can effectively inhibit pro-oncogenic molecular targets underpinning PDACs pathogenesis and progression. One such target is c-RAF, a downstream effector of RAS that is considered essential for the oncogenic growth and survival of mutant RAS-driven cancers (including KRASMT PDAC). Herein, we demonstrate how a novel cell-penetrating peptide disruptor (DRx-170) of the c-RAF–PDE8A protein–protein interaction (PPI) represents a differentiated approach to exploiting the c-RAF–cAMP/PKA signaling axes and treating KRAS–c-RAF dependent PDAC. Through disrupting the c-RAF–PDE8A protein complex, DRx-170 promotes the inactivation of c-RAF through an allosteric mechanism, dependent upon inactivating PKA phosphorylation. DRx-170 inhibits cell proliferation, adhesion and migration of a KRASMT PDAC cell line (PANC1), independent of ERK1/2 activity. Moreover, combining DRx-170 with afatinib significantly enhances PANC1 growth inhibition in both 2D and 3D cellular models. DRx-170 sensitivity appears to correlate with c-RAF dependency. This proof-of-concept study supports the development of DRx-170 as a novel and differentiated strategy for targeting c-RAF activity in KRAS–c-RAF dependent PDAC.
| Item Type: | Articles |
|---|---|
| Additional Information: | Tis work was supported by Wellcome Trust (204820/Z/16/Z): CMB, GSB, Medical Research Council (MC_PC_19039): CMB, GSB. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Sin, Dr Angie and Ling, Miss Jiayue and Baillie, Professor George and Phanthaphol, Miss Nattaporn and Rebus, Ms Selma and Blair, Dr Connor and Chang, Professor David and Cooke, Mr Sean and Biankin, Professor Andrew and Kyurkchieva, Ms Elka and Wright, Mr Tom and Herbert, Dr Katharine |
| Creator Roles: | Blair, C.Conceptualization, Methodology, Investigation, Visualization, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing Baillie, G.Conceptualization, Resources, Funding acquisition, Project administration, ["credit_typename_" not defined], Supervision, Writing – review and editing Cooke, S.Conceptualization, Methodology, Investigation, Visualization, Project administration, Writing – original draft, Writing – review and editing Chang, D.Conceptualization, Resources, Project administration, Supervision Biankin, A.Conceptualization, Resources Wright, T.Methodology, Investigation Phanthaphol, N.Methodology, Investigation Ling, J.Investigation Kyurkchieva, E.Investigation Sin, A.Investigation Herbert, K.Investigation Rebus, S.Investigation |
| Authors: | Cooke, S. F., Wright, T. A., Sin, Y. Y., Ling, J., Kyurkchieva, E., Phanthaphol, N., McSkimming, T., Herbert, K., Rebus, S., Biankin, A. V., Chang, D. K., Baillie, G. S., and Blair, C. M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Scientific Reports |
| Publisher: | Nature Research |
| ISSN: | 2045-2322 |
| ISSN (Online): | 2045-2322 |
| Copyright Holders: | This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024 |
| First Published: | First published in Scientific Reports 14: 8998 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information