Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer

Nat Med. 2019 Jan;25(1):111-118. doi: 10.1038/s41591-018-0264-7. Epub 2018 Nov 26.

Abstract

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Aurora Kinase A / metabolism*
  • Cell Count
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology*
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Mutation / genetics
  • Neoplasm, Residual / drug therapy
  • Nuclear Proteins / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*

Substances

  • Cell Cycle Proteins
  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • TPX2 protein, human
  • EGFR protein, human
  • ErbB Receptors
  • Aurora Kinase A