Therapy-induced tumour secretomes promote resistance and tumour progression

Nature. 2015 Apr 16;520(7547):368-72. doi: 10.1038/nature14336. Epub 2015 Mar 25.

Abstract

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.

Publication types

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

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Anaplastic Lymphoma Kinase
  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Clone Cells / drug effects
  • Clone Cells / pathology
  • Disease Progression*
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Enzyme Activation / drug effects
  • ErbB Receptors / antagonists & inhibitors
  • Female
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Melanoma / drug therapy
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Metabolome / drug effects*
  • Mice
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Metastasis / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-fos / deficiency
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Signal Transduction / drug effects
  • Tumor Microenvironment / drug effects

Substances

  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-fos
  • fos-related antigen 1
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt

Associated data

  • GEO/GSE64741