Disruption of the pro‑oncogenicc‑RAF–PDE8A complex represents a differentiated approach to treating KRAS–c‑RAF dependent PDAC

Q: Why is new therapy needed for pancreatic ductal adenocarcinoma (PDAC)?

PDAC is aggressive and resistant to treatment, with a late onset of symptoms and limited reliable biomarkers leading to metastatic diagnoses. Current standard-of-care regimens often fail to extend median survival beyond about one year.

Q: What is the biological target of this study?

The study focuses on c-RAF as a downstream effector of RAS and on the c-RAF–PDE8A protein–protein interaction involved in c-RAF-driven signaling relevant to KRAS–c-RAF dependent PDAC.

Q: How does DRx-170 affect c-RAF and cancer cell behavior?

DRx-170 disrupts the c-RAF–PDE8A protein complex and promotes c-RAF inactivation through an allosteric mechanism dependent on inactivating PKA phosphorylation. It reduces proliferation, adhesion, and migration in KRASMT PDAC cells and can enhance effects when combined with afatinib.

Sep 21, 2026

Uploaded by Ava Thompson

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal and treatment resistant, with advanced-stage patients facing limited options and a very low 5-year survival rate. This study targets c-RAF, a RAS downstream effector implicated in oncogenic growth and survival, and focuses on the c-RAF–PDE8A protein–protein interaction. A novel cell-penetrating disruptor peptide, DRx-170, disrupts the complex and promotes allosteric inactivation of c-RAF via PKA phosphorylation. DRx-170 inhibits proliferation, adhesion, and migration in KRASMT PDAC cells and enhances growth inhibition when combined with afatinib in 2D and 3D models, with sensitivity correlating to c-RAF dependency.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Background and unmet need

Target rationale: c-RAF and c-RAF–PDE8A signaling

DRx-170 mechanism and cellular effects

Combination with afatinib and model validation

Implications for targeted therapy in KRAS–c-RAF dependent PDAC

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Disruption of the pro‑oncogenicc‑RAF–PDE8A complex represents a differentiated approach to treating KRAS–c‑RAF dependent PDAC Sean F. Cooke1, Thomas A. Wright1, Yuan Yan Sin1, Jiayue Ling1, Elka Kyurkchieva1, Nattaporn Phanthaphol3, Thomas Mcskimming1, Katharine Herbert2, Selma Rebus2, Andrew V. Biankin2, David K. Chang2, George S. Baillie 1 & Connor M. Blair1* 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. Keywords Pancreatic ductal adenocarcinoma, KRAS, c-RAF-PDE8A, Disruptor peptide, Protein–protein interaction Abbreviations PDAC PAADNSCLC CRC SOC MT EGFR/ERBB Η/Κ/NRASA/B/c-RAFERK1/2 MEK1/2 PDE8A Pancreatic ductal adenocarcinoma Pancreatic adenocarcinoma Non-small cell lung cancer Colorectal cancer Standard of care Mutant Epidermal growth factor receptor family Rat sarcoma virus protein family Rapidly accelerated fibrosarcoma serine/threonine protein kinase family Mitogen-activated protein kinase Mitogen-activated protein kinase kinase Phosphodiesterase 8A 1College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK. 2Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK. 3Siriraj Centre of Research Excellence for Cancer Immunotherapy, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.* email: [connor.blair@glasgow.ac.uk](connor.blair@glasgow.ac.uk) [www. nature.com/scientificreports/](www. nature.com/scientificreports/) PKA Protein kinase A cAMP Cyclic adenosine monophosphate ATP Adenosine triphosphate MBP Myosin binding protein GST Glutathione s-transferase PLA Proximity ligase assay RTCA Real-time cellular analysis Accounting for >90% of pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and treatment resistant malignancy that presents advanced staged patients with a 5 year survival rate of < 5%1. The notoriously late onset of symptoms, coupled with the severe lack of reliable biomarkers, often results inpatients being diagnosed when the cancer has already metastasised. Consequently, current ‘standard of care’(SOC: gemcitabine, gemcitabine + nab-paclitaxel, FOLFIRINOX) is often unable to extend median survival rates beyond 1-year2–4. Driven by significant advances in precision medicine, and associated patient biomarker stratification platforms, next-generation targeted therapeutics are overtaking SOC chemotherapeutics in the pancreatic can

FAQs

Why is new therapy needed for pancreatic ductal adenocarcinoma (PDAC)?

PDAC is aggressive and resistant to treatment, with a late onset of symptoms and limited reliable biomarkers leading to metastatic diagnoses. Current standard-of-care regimens often fail to extend median survival beyond about one year.

What is the biological target of this study?

The study focuses on c-RAF as a downstream effector of RAS and on the c-RAF–PDE8A protein–protein interaction involved in c-RAF-driven signaling relevant to KRAS–c-RAF dependent PDAC.

How does DRx-170 affect c-RAF and cancer cell behavior?

DRx-170 disrupts the c-RAF–PDE8A protein complex and promotes c-RAF inactivation through an allosteric mechanism dependent on inactivating PKA phosphorylation. It reduces proliferation, adhesion, and migration in KRASMT PDAC cells and can enhance effects when combined with afatinib.

Sep 21, 2026

Uploaded by Ava Thompson