HER2-L755S mutation induces hyperactive MAPK and PI3K-mTOR signaling, leading to resistance to HER2 tyrosine kinase inhibitor treatment

  • Cell Cycle. 2019 Jul;18(13):1513-1522. doi: 10.1080/15384101.2019.1624113.
Jiayao Li  1  2 ,  Qian Xiao  1  2 ,  Yi Bao  3 ,  Wenyu Wang  3 ,  Jianyuan Goh  3 ,  Panpan Wang  1  2 ,  Qiang Yu  2  3
Affiliations
  • 1. a School of Pharmacy , Jinan University , Guangzhou , China.
  • 2. b Cancer Research Institute , Jinan University , Guangzhou , China.
  • 3. c Cancer Therapeutics and Stratified Oncology , Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research) , Biopolis , Singapore.
PMID: 31135266 DOI: 10.1080/15384101.2019.1624113
Abstract

L755S, a HER2 kinase domain mutation, is the most common HER2 mutation in breast Cancer associated with resistance to anti-HER2 trastuzumab treatment. Here, we showed that HER2-L755S confers hyperactivation of MAPK and PI3K/Akt/mTOR pathways and resistance to both reversible and irreversible HER2 tyrosine kinase inhibitors. We further demonstrated that the HER2 TKIs in combination with MEK Inhibitor, AZD6244, or PI3K Inhibitor, GDC0941, yield robust killing in HER2-L755S Cancer cells, indicating a novel targeted strategy to overcome HER2-L755S resistance to anti-HER2 treatment.

Keywords
HER2; L755S; combination; lapatinib; neratinib; resistance.
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