Synergistic disruption of ERα/HER2 crosstalk by endoxifen and lapatinib in breast cancer cells

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• 作者：James Chun Yip Chan ; Pei Shi Ong ; Peirong Lim…
• 关键词：Lapatinib ; Endoxifen ; ERα ; HER2 ; Combination therapy ; Breast cancer
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：79
• 期：1
• 页码：117-130
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Oncology; Pharmacology/Toxicology; Cancer Research;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-0843
• 卷排序：79

文摘

BackgroundDespite decades of clinical success, tamoxifen therapy is complicated by inter-individual variability due to CYP450 polymorphism and resistance attributed to ERα/HER2 crosstalk. Direct administration of endoxifen shows promise in circumventing obligatory CYP450 bioactivation while maintaining efficacy. Separately, disruption of the crosstalk using probe antagonists against ERα (tamoxifen) and HER2 (e.g., lapatinib) has been explored clinically. However, the efficacy of this combination may be confounded by lapatinib, a potent inactivator of CYP3A4/5 which could negate the bioactivation of tamoxifen to the active metabolite endoxifen. Additionally, in a manner analogous to tamoxifen, endoxifen is similarly not immune to the development of ERα/HER2 crosstalk that could result in resistance. Simultaneous antagonism of ERα and HER2 using endoxifen and lapatinib could overcome these problems.