Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer

Cell. 2012 Apr 13;149(2):307-21. doi: 10.1016/j.cell.2012.02.053.

Abstract

Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple-negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs). RNAi knockdown of ERK or c-Myc mimicked RTK induction by MEK inhibitors, and prevention of proteasomal c-Myc degradation blocked kinome reprogramming. MEK inhibitor-induced RTK stimulation overcame MEK2 inhibition, but not MEK1 inhibition, reactivating ERK and producing drug resistance. The C3Tag GEMM for TNBC similarly induced RTKs in response to MEK inhibition. The inhibitor-induced RTK profile suggested a kinase inhibitor combination therapy that produced GEMM tumor apoptosis and regression where single agents were ineffective. This approach defines mechanisms of drug resistance, allowing rational design of combination therapies for cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Benzenesulfonates / therapeutic use
  • Benzimidazoles / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • Male
  • Mice
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism
  • Proteome / analysis*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Pyridines / therapeutic use
  • Receptor Protein-Tyrosine Kinases / genetics
  • Sorafenib

Substances

  • AZD 6244
  • Antineoplastic Agents
  • Benzenesulfonates
  • Benzimidazoles
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Proteome
  • Proto-Oncogene Proteins c-myc
  • Pyridines
  • Niacinamide
  • Sorafenib
  • Protein Kinases
  • Receptor Protein-Tyrosine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1