Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 1, pp 117–130 | Cite as

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

  • James Chun Yip Chan
  • Pei Shi Ong
  • Peirong Lim
  • Preben Xiang Long Teng
  • Eric Chun Yong Chan
Original Article
  • 275 Downloads

Abstract

Background

Despite 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.

Methods

Metabolism studies were performed in human liver microsomes to determine the extent of inhibition of tamoxifen bioactivation by lapatinib. Synergism of endoxifen and lapatinib was assessed using the combination index design in a panel of cell models exhibiting either a priori ERα/HER2 crosstalk (BT474) or acquired ERα/HER2 crosstalk (TAM-R and MCF-7/HER2).

Results

Lapatinib inhibited tamoxifen bioactivation by up to 1.8-fold. Synergistic activity was uncovered for lapatinib 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.

Conclusion

This forward-looking study extends the success of tamoxifen by exploring the effectiveness of combining the next-generation tamoxifen derivative, endoxifen with an anti-HER2 agent to combat ERα/HER2 crosstalk, and at the same time provides a solution to the predicted pharmacokinetic antagonism between lapatinib and tamoxifen.

Keywords

Lapatinib Endoxifen ERα HER2 Combination therapy Breast cancer 

Abbreviations

ERα

Estrogen receptor α

HER2

Human epidermal growth factor receptor 2

CYP3A4/5

Cytochrome P450 3A4/3A5

4-OHT

4-Hydroxytamoxifen

NDMT

N-desmethyltamoxifen

CYP2D6

Cytochrome P450 2D6

CYP450

Cytochrome P450

HLM

Human liver microsomes

CLint

Intrinsic clearance

IS

Internal standard

LC/MS/MS

Liquid chromatography-tandem mass spectrometry

DRI50

Dose reduction index at 50% cytotoxicity

ANOVA

One-way analysis of variance

fa

Fraction affected

PI3K/Akt

Phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B

Supplementary material

280_2016_3211_MOESM1_ESM.pdf (33 kb)
Supplementary material 1 (PDF 32 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of Pharmacy, Faculty of ScienceNational University of SingaporeSingaporeSingapore

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