Related Experiment Video

Updated: Jun 28, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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Disruption of the pro-oncogenic c-RAF-PDE8A complex represents a differentiated approach to treating KRAS-c-RAF

Sean F Cooke1, Thomas A Wright1, Yuan Yan Sin1

  • 1College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.

Scientific Reports
|April 18, 2024
PubMed

Insights

A novel peptide, DRx-170, disrupts the c-RAF-PDE8A interaction, inhibiting pancreatic cancer cell growth. This offers a new therapeutic strategy for KRAS-mutant pancreatic ductal adenocarcinoma (PDAC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality with limited treatment options.
  • RAS-driven cancers, including KRAS-mutant PDAC, rely on c-RAF for growth and survival.
  • Targeting oncogenic molecular pathways is crucial for developing novel PDAC therapies.

Purpose of the Study:

  • To investigate the therapeutic potential of DRx-170, a novel peptide disruptor of the c-RAF-PDE8A protein-protein interaction (PPI).
  • To evaluate DRx-170's efficacy in inhibiting KRAS-c-RAF dependent PDAC.
  • To explore the combination therapy of DRx-170 with afatinib for enhanced PDAC treatment.

Main Methods:

  • Utilized a novel cell-penetrating peptide, DRx-170, designed to disrupt the c-RAF-PDE8A PPI.
  • Assessed DRx-170's impact on c-RAF inactivation via an allosteric mechanism dependent on PKA phosphorylation.
  • Evaluated DRx-170's effects on KRAS-mutant PDAC cell line (PANC1) proliferation, adhesion, and migration in 2D and 3D models.
  • Investigated the synergistic effect of combining DRx-170 with afatinib.

Main Results:

  • DRx-170 effectively inhibited proliferation, adhesion, and migration of PANC1 cells, independent of ERK1/2 activity.
  • Disruption of the c-RAF-PDE8A complex by DRx-170 led to c-RAF inactivation.
  • Combination therapy with DRx-170 and afatinib significantly enhanced PANC1 growth inhibition.
  • DRx-170 sensitivity correlated with c-RAF dependency in PDAC models.

Conclusions:

  • DRx-170 represents a novel therapeutic strategy targeting the c-RAF-cAMP/PKA signaling axis in KRAS-c-RAF dependent PDAC.
  • The peptide's ability to inhibit cancer cell functions and enhance existing therapies shows promise.
  • Further development of DRx-170 is warranted for treating KRAS-mutant PDAC.
Keywords:
Disruptor peptideKRASPancreatic ductal adenocarcinomaProtein–protein interactionc-RAF-PDE8A

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