title: Synergistic disruption of ERα/HER2 crosstalk by endoxifen and lapatinib in breast cancer cells.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: James Chun Yip
authors.initials: JC
authors.lastname: Chan
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Pei Shi
authors.initials: PS
authors.lastname: Ong
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Peirong
authors.initials: P
authors.lastname: Lim
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Preben Xiang Long
authors.initials: PX
authors.lastname: Teng
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore. phaccye@nus.edu.sg.
authors.forename: Eric Chun Yong
authors.identifier: http://orcid.org/0000-0001-6107-9072
authors.initials: EC
authors.lastname: Chan
mesh_terms: D065767:Activation, Metabolic; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000502:physiology; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D006801:Humans; D000077341:Lapatinib; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D047628:Estrogen Receptor alpha; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C506487:ESR1 protein, human; C055492:4-hydroxy-N-desmethyltamoxifen; C508053:ERBB2 protein, human
keywords: Breast cancer; Combination therapy; ERα; Endoxifen; HER2; Lapatinib