An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer

Cancer Discov. 2017 Jun;7(6):575-585. doi: 10.1158/2159-8290.CD-16-1431. Epub 2017 Mar 8.


We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib.Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2-mutant breast cancer upon clinical progression on neratinib. We speculate that HER2T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2-activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575-85. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539.

Trial registration: NCT01953926.

Publication types

  • Case Reports

MeSH terms

  • Afatinib
  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Humans
  • Middle Aged
  • Mutation
  • Phenotype
  • Protein Kinase Inhibitors / therapeutic use*
  • Quinazolines / pharmacology
  • Quinolines / therapeutic use*
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / genetics*


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Quinazolines
  • Quinolines
  • Afatinib
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • neratinib

Associated data