TY - JOUR
T1 - Neratinib plus dasatinib is highly synergistic in HER2-positive breast cancer in vitro and in vivo
AU - Conlon, Neil T.
AU - Roche, Sandra
AU - Mahdi, Amira F.
AU - Browne, Alacoque
AU - Breen, Laura
AU - Gaubatz, Johanna
AU - Meiller, Justine
AU - O'Neill, Fiona
AU - O'Driscoll, Lorraine
AU - Cremona, Mattia
AU - Hennessy, Bryan T.
AU - Eli, Lisa D.
AU - Crown, John
AU - Collins, Denis M.
N1 - Publisher Copyright:
© 2024
PY - 2024/11
Y1 - 2024/11
N2 - Background: HER2-targeted therapies have revolutionised the treatment of HER2-positive breast cancer. However, de novo resistance or the emergence of acquired resistance is a persistent clinical problem. Here we report that neratinib, an irreversible pan-HER inhibitor, in combination with the multi-kinase inhibitor dasatinib, currently used to treat certain leukemias, has strong anti-proliferative effects against models of HER2-positive breast cancer that are innately resistant to trastuzumab or have acquired resistance to neratinib. Methods: Neratinib plus dasatinib was examined in a panel of 20 breast cancer cell lines, including HER2-positive, estrogen-receptor-positive, triple negative, and acquired HER2-targeted therapy resistant models. Drug effects on migration and apoptosis induction was evaluated and signaling alterations were determined by reverse phase protein array (RPPA). In vivo efficacy was examined using orthotopically-implanted HCC1954 cells. Results: Synergy was observed in cell lines innately resistant to trastuzumab, models with acquired resistance to neratinib, and in triple negative breast cancer cell lines. Further investigation showed that neratinib plus dasatinib induced apoptosis and inhibited cell migration to a greater degree than either drug alone. RPPA revealed that the combination caused suppression of key survival signaling through EGFR, Akt, and MAPK inhibition. In vivo, neratinib plus dasatinib was well tolerated and had a prolonged anti-tumor effect against HCC1954 xenografts. Conclusions: This study provides a strong pre-clinical rationale for the clinical investigation neratinib and dasatinib in HER2+ breast cancer.
AB - Background: HER2-targeted therapies have revolutionised the treatment of HER2-positive breast cancer. However, de novo resistance or the emergence of acquired resistance is a persistent clinical problem. Here we report that neratinib, an irreversible pan-HER inhibitor, in combination with the multi-kinase inhibitor dasatinib, currently used to treat certain leukemias, has strong anti-proliferative effects against models of HER2-positive breast cancer that are innately resistant to trastuzumab or have acquired resistance to neratinib. Methods: Neratinib plus dasatinib was examined in a panel of 20 breast cancer cell lines, including HER2-positive, estrogen-receptor-positive, triple negative, and acquired HER2-targeted therapy resistant models. Drug effects on migration and apoptosis induction was evaluated and signaling alterations were determined by reverse phase protein array (RPPA). In vivo efficacy was examined using orthotopically-implanted HCC1954 cells. Results: Synergy was observed in cell lines innately resistant to trastuzumab, models with acquired resistance to neratinib, and in triple negative breast cancer cell lines. Further investigation showed that neratinib plus dasatinib induced apoptosis and inhibited cell migration to a greater degree than either drug alone. RPPA revealed that the combination caused suppression of key survival signaling through EGFR, Akt, and MAPK inhibition. In vivo, neratinib plus dasatinib was well tolerated and had a prolonged anti-tumor effect against HCC1954 xenografts. Conclusions: This study provides a strong pre-clinical rationale for the clinical investigation neratinib and dasatinib in HER2+ breast cancer.
KW - Breast cancer
KW - Dasatinib
KW - HER2-positive
KW - Neratinib
KW - Targeted therapies
KW - Tyrosine kinase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85202077868&partnerID=8YFLogxK
U2 - 10.1016/j.tranon.2024.102073
DO - 10.1016/j.tranon.2024.102073
M3 - Article
AN - SCOPUS:85202077868
SN - 1936-5233
VL - 49
SP - 102073
JO - Translational Oncology
JF - Translational Oncology
M1 - 102073
ER -