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Updated: Jun 13, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

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

Published on: July 17, 2019

The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy

Stephen L Abrams1, Linda S Steelman, John G Shelton

  • 1Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.

Cell Cycle (Georgetown, Tex.)
|May 4, 2010
PubMed

Insights

Targeting the Raf/MEK/ERK and PI3K/Akt/mTOR pathways may treat drug-resistant cancers. The Raf/MEK/ERK pathway significantly impacts drug sensitivity, while Akt-1 is crucial for long-term growth and resistance.

Area of Science:

  • Cellular signaling pathways
  • Cancer biology
  • Drug resistance mechanisms

Background:

  • The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways regulate critical cellular processes.
  • Understanding these pathways is vital for cancer therapy.

Purpose of the Study:

  • To investigate the role of Raf/MEK/ERK and PI3K/Akt/mTOR pathways in drug resistance.
  • To examine their effects on cell proliferation, apoptosis, and sensitivity to inhibitors.

Main Methods:

  • Utilized FL/DeltaAkt-1:ER*(Myr(+)) + DeltaRaf-1:AR cells, conditionally transformed for growth upon Raf and Akt activation.
  • Isolated drug-resistant cells by exposing cells to doxorubicin.
  • Assessed IC50 values for doxorubicin and evaluated effects of pathway activation and inhibition.

Main Results:

  • Raf-1 activation increased doxorubicin IC50 80-fold in resistant cells; Akt-1 activation alone had no effect on IC50.
  • Akt-1 activation enhanced proliferation and clonogenicity in the presence of chemotherapeutic drugs.
  • Doxorubicin-induced apoptosis in resistant cells was enhanced by mTOR and MEK inhibitors.

Conclusions:

  • The Raf/MEK/ERK pathway profoundly influences sensitivity to chemotherapeutic drugs.
  • Akt-1 activation is essential for long-term growth and drug resistance.
  • Targeting these signaling pathways offers a potential therapeutic strategy for drug-resistant cancers with activating mutations.

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