Journal
CANCER LETTERS
Volume 470, Issue -, Pages 161-169Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.11.026
Keywords
HER2; Breast cancer; Drug resistance; Lapatinib; Neratinib
Categories
Funding
- Ministry of Economy and Competitiveness of Spain [BFU201571371-R]
- Institute de Salud Carlos III through the Spanish Cancer Centers Network Program [RD12/0036/0003]
- CIBERONC
- Scientific Foundation of the Spanish Association Against Cancer (AECC)
- CRIS Cancer Foundation
- Cancer Research Institute
- European Community through the Regional Development Funding Program (FEDER)
- Consejeria de Educacion of the Castilla and Leon Autonomous Government
- MINECO [BES-2016-077748]
- ALMOM
- ACMUMA
- UCCTA
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Small molecule inhibitors (TKIs) of HER2 have demonstrated clinical benefit in HER2-positive breast tumors. One of them, lapatinib, is used once advanced tumors become refractory to the HER2 antibody trastuzumab. Another one, neratinib, has shown benefit in high-risk early-stage breast cancer after trastuzumab-based therapies. A common characteristic is that patients are formerly treated with trastuzumab. We have explored whether trastuzumab previous therapy affects its antitumoral action. Long time exposure of the HER2 + cell line BT474 to trastuzumab resulted in trastuzumab-insensitive cells (BTRH cells). While treatment of wild type BT474 cells with lapatinib or neratinib resulted in decreased viability, BTRH cells were resistant to the action of these TKIs. Analogous results were obtained using trastuzumab-resistant cells derived from a PDX. Functional transcriptomic analyses and biochemical studies demonstrated that the TKIs caused DNA damage and apoptosis in wild type cells, but not in BTRH. Moreover, previous treatment with trastuzumab impairs response to small TKIs, by eliminating their proapoptotic action. Moreover, actioning on the apoptotic machinery using a chemical library of proapoptotic compounds led to the identification of clinical-stage drugs that may be used to fight trastuzumab-TKI resistance.
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