What is it about?
Despite decades of clinical success, tamox-ifen 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 bio-activation while maintaining efficacy. Separately, disrup-tion 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 tamox-ifen 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 problem
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Why is it important?
Lapatinib inhibited tamoxifen bioactivation by up to 1.8-fold. Synergistic activity was uncovered for lapat-inib and endoxifen against BT474, TAM-R and MCF-7/HER2 models of ERα/HER2 crosstalk. Western blot confirmed that endoxifen and lapatinib disrupted this crosstalk.
Perspectives
This forward-looking study extends the suc-cess of tamoxifen by exploring the effectiveness of com-bining the next-generation tamoxifen derivative, endoxifen with an anti-HER2 agent to combat ERα/HER2 cross-talk, and at the same time provides a solution to the pre-dicted pharmacokinetic antagonism between lapatinib and tamoxifen.
Dr Eric Chun Yong Chan
National University of Singapore
Read the Original
This page is a summary of: Synergistic disruption of ERα/HER2 crosstalk by endoxifen and lapatinib in breast cancer cells, Cancer Chemotherapy and Pharmacology, December 2016, Springer Science + Business Media,
DOI: 10.1007/s00280-016-3211-7.
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