Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells

Cancer Cell. 2014 Aug 11;26(2):207-21. doi: 10.1016/j.ccr.2014.05.019. Epub 2014 Jul 24.

Abstract

Pathway-targeted cancer drugs can produce dramatic responses that are invariably limited by the emergence of drug-resistant cells. We found that many drug-treated "oncogene-addicted" cancer cells engage a positive feedback loop leading to Stat3 activation, consequently promoting cell survival and limiting overall drug response. This was observed in cancer cells driven by diverse activated kinases, including EGFR, HER2, ALK, and MET, as well as mutant KRAS. Specifically, MEK inhibition led to autocrine activation of Stat3 via the FGF receptor and JAK kinases, and pharmacological inhibition of MEK together with JAK and FGFR enhanced tumor regression. These findings suggest that inhibition of a Stat3 feedback loop may augment the response to a broad spectrum of drugs that target pathways of oncogene addiction.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / mortality
  • Adenocarcinoma of Lung
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-6 / metabolism
  • Janus Kinase 1 / metabolism
  • Kaplan-Meier Estimate
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Mice
  • Mice, SCID
  • Mutation
  • Oncogenes
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Pyrazoles / pharmacology
  • Pyridazines / pharmacology
  • Quinazolines / pharmacology
  • Receptors, Fibroblast Growth Factor / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics

Substances

  • Antineoplastic Agents
  • IL6 protein, human
  • INCB018424
  • Imidazoles
  • Interleukin-6
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Pyrazoles
  • Pyridazines
  • Quinazolines
  • Receptors, Fibroblast Growth Factor
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • ponatinib
  • Erlotinib Hydrochloride
  • Phosphatidylinositol 3-Kinases
  • EGFR protein, human
  • ErbB Receptors
  • JAK1 protein, human
  • Janus Kinase 1
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins