Related Experiment Video

Updated: Feb 27, 2026

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

3.4K

Co-dependency between KRAS addiction and ARHGEF2 promotes an adaptive escape from MAPK pathway inhibition

Oliver A Kent1, Maria-Jose Sandi1, Robert Rottapel1,2,3,4,5

  • 1Princess Margaret Cancer Centre, University Health Network, Toronto Medical Discovery Tower, University of Toronto , Toronto , Canada.

Small Gtpases
|June 29, 2017
PubMed

Insights

Pancreatic cancer cells with KRAS addiction depend on ARHGEF2. Targeting ARHGEF2 may enhance MAPK inhibitors for treating RAS-dependent pancreatic cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Oncogenic KRAS drives pancreatic cancer proliferation and survival via effector pathways like MAPK.
  • KRAS-transformed cells display oncogene addiction, relying on sustained RAS activity for malignancy.
  • ARHGEF2 (a RHO guanine exchange factor) is crucial for RAS-transformed pancreatic tumor growth and survival.

Purpose of the Study:

  • To investigate the dependency of KRAS-addicted pancreatic cancer cells on ARHGEF2 expression.
  • To explore the role of ARHGEF2 in desensitizing cancer cells to MEK inhibition.
  • To elucidate the feedback loop involving ARHGEF2, ERK phosphorylation, and ARHGEF2 promoter activity.

Main Methods:

  • Assessing the dependency of KRAS-addicted pancreatic cancer cells on ARHGEF2 expression.
  • Evaluating the effect of enforced ARHGEF2 expression on MEK inhibitor sensitivity.
  • Analyzing the feedback loop mechanism involving ERK phosphorylation and ARHGEF2 promoter activity.

Main Results:

  • Pancreatic cancer cells with KRAS addiction show significant dependence on ARHGEF2 expression.
  • Enforced ARHGEF2 expression desensitizes cells to MEK inhibitors.
  • ARHGEF2 initiates a positive feedback loop activating ERK phosphorylation and the ARHGEF2 promoter.

Conclusions:

  • ARHGEF2 is a critical factor in KRAS-addicted pancreatic cancer.
  • Targeting ARHGEF2 expression could overcome resistance to MEK inhibitors.
  • Combining ARHGEF2 targeting with MAPK inhibitors may improve treatment efficacy for RAS-dependent pancreatic cancers.
Keywords:
ARHGEF2GEF-H1KRASMEK inhibitionRas dependencyoncogene addictionpancreatic cancer

More Related Videos

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods07:49

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

Published on: July 17, 2019

6.6K
Reliably Engineering and Controlling Stable Optogenetic Gene Circuits in Mammalian Cells09:20

Reliably Engineering and Controlling Stable Optogenetic Gene Circuits in Mammalian Cells

Published on: July 6, 2021

2.8K

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
8.8K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.4K
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
7.4K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.9K
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
5.6K
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
8.7K