AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs

Cancer Res. 2014 Oct 15;74(20):5878-90. doi: 10.1158/0008-5472.CAN-14-1009. Epub 2014 Aug 14.

Abstract

Molecularly targeted drug therapies have revolutionized cancer treatment; however, resistance remains a major limitation to their overall efficacy. Epithelial-to-mesenchymal transition (EMT) has been linked to acquired resistance to tyrosine kinase inhibitors (TKI), independent of mutational resistance mechanisms. AXL is a receptor tyrosine kinase associated with EMT that has been implicated in drug resistance and has emerged as a candidate therapeutic target. Across 643 human cancer cell lines that were analyzed, elevated AXL was strongly associated with a mesenchymal phenotype, particularly in triple-negative breast cancer and non-small cell lung cancer. In an unbiased screen of small-molecule inhibitors of cancer-relevant processes, we discovered that AXL inhibition was specifically synergistic with antimitotic agents in killing cancer cells that had undergone EMT and demonstrated associated TKI resistance. However, we did not find that AXL inhibition alone could overcome acquired resistance to EGFR TKIs in the EMT setting, as previously reported. These findings reveal a novel cotreatment strategy for tumors displaying mesenchymal features that otherwise render them treatment refractory.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Axl Receptor Tyrosine Kinase
  • CDC2 Protein Kinase
  • Cisplatin / pharmacology*
  • Cyclin-Dependent Kinases / metabolism
  • Docetaxel
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Epithelial-Mesenchymal Transition
  • Erlotinib Hydrochloride
  • HeLa Cells
  • Humans
  • Mesoderm / pathology
  • Mice, Nude
  • Mitosis / drug effects
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Quinazolines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Taxoids / pharmacology
  • Transforming Growth Factor beta / physiology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Proto-Oncogene Proteins
  • Quinazolines
  • Taxoids
  • Transforming Growth Factor beta
  • Docetaxel
  • Erlotinib Hydrochloride
  • Receptor Protein-Tyrosine Kinases
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases
  • Cisplatin
  • Axl Receptor Tyrosine Kinase