Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer

被引:145
作者
Canonici, Alexandra [1 ]
Gijsen, Merel [2 ]
Mullooly, Maeve [4 ,5 ]
Bennett, Ruth [2 ]
Bouguern, Noujoude [2 ]
Pedersen, Kasper [1 ]
O'Brien, Neil A. [6 ]
Roxanis, Ioannis [7 ,8 ]
Li, Ji-Liang [3 ]
Bridge, Esther [3 ]
Finn, Richard [6 ]
Slamon, Dennis [6 ]
McGowan, Patricia [4 ,5 ]
Duffy, Michael J. [4 ,5 ]
O'Donovan, Norma [1 ]
Crown, John [1 ,4 ,5 ]
Kong, Anthony [2 ]
机构
[1] Dublin City Univ, Natl Inst Cellular Biotechnol, Dublin 9, Ireland
[2] Univ Oxford, Human Epidermal Growth Factor Grp, Oxford OX1 2JD, England
[3] Univ Oxford, Weatherall Inst Mol Med, Dept Oncol, Growth Factor Grp, Oxford OX1 2JD, England
[4] St Vincents Univ Hosp, Clin Res Ctr, Dublin 4, Ireland
[5] Univ Coll Dublin, UCD Sch Med & Med Sci, Conway Inst, Dublin 2, Ireland
[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA
[7] Oxford Univ Hosp, Dept Cellular Pathol, Oxford, England
[8] Oxford Biomed Res Ctr, Oxford, England
基金
爱尔兰科学基金会; 英国医学研究理事会;
关键词
breast cancer; HER2/ErbB2; trastuzumab (Herceptin); neratinib; panHER inhibitor; GROWTH-FACTOR; CELL-LINES; ADJUVANT CHEMOTHERAPY; LAPATINIB; HETERODIMERIZATION; COMBINATION; INHIBITOR; AMPLIFICATION; CONTRIBUTES; DETERMINANT;
D O I
10.18632/oncotarget.1148
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab.
引用
收藏
页码:1592 / 1605
页数:14
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