HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway

Nat Commun. 2021 Nov 18;12(1):6667. doi: 10.1038/s41467-021-27093-y.


Inhibition of HER2 in HER2-amplified breast cancer has been remarkably successful clinically, as demonstrated by the efficacy of HER-kinase inhibitors and HER2-antibody treatments. Whilst resistance to HER2 inhibition is common in the metastatic setting, the specific programs downstream of HER2 driving resistance are not established. Through genomic profiling of 733 HER2-amplified breast cancers, we identify enrichment of somatic alterations that promote MEK/ERK signaling in metastatic tumors with shortened progression-free survival on anti-HER2 therapy. These mutations, including NF1 loss and ERBB2 activating mutations, are sufficient to mediate resistance to FDA-approved HER2 kinase inhibitors including tucatinib and neratinib. Moreover, resistant tumors lose AKT dependence while undergoing a dramatic sensitization to MEK/ERK inhibition. Mechanistically, this driver pathway switch is a result of MEK-dependent activation of CDK2 kinase. These results establish genetic activation of MAPK as a recurrent mechanism of anti-HER2 therapy resistance that may be effectively combated with MEK/ERK inhibitors.

Publication types

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

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Lapatinib / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Mutation
  • Oxazoles / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / pharmacology
  • Quinazolines / pharmacology
  • Quinolines / pharmacology
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Tumor Escape / drug effects*


  • Oxazoles
  • Protein Kinase Inhibitors
  • Pyridines
  • Quinazolines
  • Quinolines
  • Lapatinib
  • tucatinib
  • Receptor, ErbB-2
  • neratinib