Related Experiment Video

Updated: May 5, 2026

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
07:42

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

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Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer

James S Duncan1, Martin C Whittle, Kazuhiro Nakamura

  • 1Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.

Cell
|April 17, 2012
PubMed

Insights

Tumors develop resistance to MEK inhibitors by activating receptor tyrosine kinases (RTKs). Combination therapy targeting these RTKs can overcome resistance and induce tumor regression in triple-negative breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Proteomics

Background:

  • Kinase inhibitors show limited efficacy in cancer due to resistance mechanisms.
  • Triple-negative breast cancer (TNBC) remains a challenging malignancy with few targeted therapies.

Purpose of the Study:

  • To investigate kinome reprogramming in response to MEK inhibition in TNBC.
  • To identify mechanisms of drug resistance and explore rational combination therapies.

Main Methods:

  • Quantitative proteomics was employed to analyze kinome activity in TNBC cells and genetically engineered mouse models (GEMMs).
  • RNA interference (RNAi) was used to assess the roles of ERK and c-Myc in resistance.
  • Proteasomal degradation pathways were investigated.

Main Results:

  • MEK inhibition led to ERK activity loss, c-Myc degradation, and subsequent induction of receptor tyrosine kinases (RTKs).
  • RTK induction mediated resistance to MEK inhibitors by reactivating ERK, particularly MEK2.
  • Combination therapy targeting RTKs induced tumor apoptosis and regression in GEMMs.

Conclusions:

  • Understanding kinome reprogramming is crucial for overcoming drug resistance in cancer.
  • Targeting RTKs in combination with MEK inhibitors offers a promising strategy for TNBC treatment.
  • This study provides a framework for rational drug combination design in oncology.

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