Journal
CELL CYCLE
Volume 18, Issue 13, Pages 1513-1522Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2019.1624113
Keywords
HER2; L755S; resistance; lapatinib; neratinib; combination
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Funding
- Graduate Scholarship of Jinan University
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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.
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