Abstract
Acquired resistance to lapatinib, an inhibitor of EGFR and HER2 kinases, is common. We found that reactivation of EGFR, HER2 and HER3 occurred within 24 hours of lapatinib treatment after their initial dephosphorylation. This was associated with increased expression of NRG1 in cells treated with lapatinib. Exogenous NRG1 partially rescued breast cancer cells from growth inhibition by lapatinib. In addition, both parental and lapatinib-resistant breast cancer cells were sensitive to SGP1, which inhibits binding of NRG1 and other HER3 ligands. Addition of pertuzumab to lapatinib further inhibited NRG1-induced signalling, which was not fully inhibited by either drug alone. In animal model, a combination of pertuzumab to lapatinib induced a greater tumor regression than either lapatinib or pertuzumab monotherapy. This novel combination treatment may provide a promising strategy in clinical HER2-targeted therapy and may inhibit a subset of lapatinib-resistant breast cancer, although the group of patients that will respond to this therapy requires further stratification.
DOI
10.18632/oncotarget.3296
Publication Date
2015-03-20
Publication Title
Oncotarget
Volume
6
Issue
8
Publisher
Impact Journals, LLC
ISSN
1949-2553
Embargo Period
2024-11-19
First Page
5678
Last Page
5694
Recommended Citation
Leung, W., Roxanis, I., Sheldon, H., Buffa, F., & et al. (2015) 'Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1-mediated signalling in HER2-amplified breast cancer', Oncotarget, 6(8), pp. 5678-5694. Impact Journals, LLC: Available at: https://doi.org/10.18632/oncotarget.3296
