title: EGFR/HER2 inhibitor AEE788 increases ER-mediated transcription in HER2/ER-positive breast cancer cells but functions synergistically with endocrine therapy.
abstract: BACKGROUND
  Cross-talk between receptor tyrosine kinases and the oestrogen receptor (ER) is implicated in resistance to endocrine therapy. We investigated whether AEE788 (a combined inhibitor of EGFR, HER2 and VEGFR) plus tamoxifen or letrozole enhanced the individual anti-tumour effects of these agents.
  
  
  METHODS
  Breast cancer cell lines modelling endocrine-resistant and -sensitive disease were engineered to express aromatase (A) and examined using proliferation, western blotting and ER-alpha transcription assays.
  
  
  RESULTS
  AEE788 enhanced the anti-proliferative effect of tamoxifen and letrozole in ER(+) cell lines (MCF-7 2A, ZR75.1 A3 and BT474 A3). This associated with an elevated G1 arrest and nuclear accumulation of p27. It is noteworthy that AEE788 alone or in combination with endocrine therapy increased the expression of progesterone receptor (PGR) and TFF1 in BT474 A3 cells. This may indicate a mechanism of resistance to AEE788 in ER(+)/HER2(+) breast cancers. In a ZR75.1 A3 xenograft, AEE788 alone or in combination with tamoxifen provided no further benefit compared with letrozole. However, letrozole plus AEE788 produced a significantly greater inhibition of tumour growth compared with letrozole alone.
  
  
  CONCLUSIONS
  These data suggest that AEE788 plus letrozole in breast cancer overexpressing HER2 may provide superior anti-tumour activity, compared with single agents.
authors.affiliation: Breakthrough Breast Cancer Centre, Institute of Cancer Research, London, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Evans
authors.forename: S
authors.initials: S
authors.lastname: Pancholi
authors.forename: I
authors.initials: I
authors.lastname: Farmer
authors.forename: A
authors.initials: A
authors.lastname: Thornhill
authors.forename: D B
authors.initials: DB
authors.lastname: Evans
authors.forename: S R
authors.initials: SR
authors.lastname: Johnston
authors.forename: M
authors.initials: M
authors.lastname: Dowsett
authors.forename: L-A
authors.initials: LA
authors.lastname: Martin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D000077289:Letrozole; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D009570:Nitriles / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000008:administration & dosage*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014230:Triazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001141:Aromatase; D066246:ErbB Receptors; D000077289:Letrozole; D009570:Nitriles; D011687:Purines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; D014230:Triazoles; C508053:ERBB2 protein, human; C489254:AEE 788
references.citation: Endocr Rev. 2008 Apr;29(2):217-33
references.pmid: 18216219
references.citation: Cancer Res. 2001 Sep 1;61(17):6583-91
references.pmid: 11522658
references.citation: Eur J Cancer Clin Oncol. 1984 Nov;20(11):1419-24
references.pmid: 6542011
references.citation: Cancer Res. 2001 Dec 1;61(23):8452-8
references.pmid: 11731427
references.citation: J Biol Chem. 2001 Nov 2;276(44):40888-95
references.pmid: 11527971
references.citation: EMBO J. 2002 Jul 1;21(13):3390-401
references.pmid: 12093740
references.citation: J Natl Cancer Inst. 2007 May 2;99(9):694-705
references.pmid: 17470737
references.citation: J Biol Chem. 2000 Aug 18;275(33):25146-54
references.pmid: 10831586
references.citation: J Clin Oncol. 2001 Sep 15;19(18):3808-16
references.pmid: 11559718
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11217-22
references.pmid: 10500157
references.citation: Lancet. 2005 Jan 1-7;365(9453):60-2
references.pmid: 15639680
references.citation: Cancer Res. 1983 Jan;43(1):349-54
references.pmid: 6847777
references.citation: J Clin Oncol. 2005 Apr 10;23(11):2469-76
references.pmid: 15753463
references.citation: J Natl Cancer Inst. 2004 Jun 16;96(12):926-35
references.pmid: 15199112
references.citation: Nat Med. 2002 Oct;8(10):1153-60
references.pmid: 12244302
references.citation: Clin Breast Cancer. 2009 Jun;9 Suppl 1:S28-36
references.pmid: 19561004
references.citation: Mol Cancer Ther. 2007 Sep;6(9):2458-67
references.pmid: 17876043
references.citation: Endocr Relat Cancer. 2005 Dec;12(4):1017-36
references.pmid: 16322340
references.citation: Cancer Res. 2008 Feb 1;68(3):826-33
references.pmid: 18245484
references.citation: J Clin Oncol. 2006 Jul 1;24(19):3019-25
references.pmid: 16754938
references.citation: Cancer Res. 2004 Jul 15;64(14):4931-41
references.pmid: 15256466
references.citation: J Biol Chem. 2003 Aug 15;278(33):30458-68
references.pmid: 12775708
references.citation: Cancer Res. 2005 Jan 1;65(1):18-25
references.pmid: 15665275
references.citation: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7795-800
references.pmid: 16682622
references.citation: Endocrinology. 2003 Nov;144(11):5105-17
references.pmid: 12960029
references.citation: J Clin Oncol. 2005 Apr 10;23(11):2477-92
references.pmid: 15767642
references.citation: Adv Enzyme Regul. 1984;22:27-55
references.pmid: 6382953
references.citation: Cancer Res. 2009 Jun 1;69(11):4716-23
references.pmid: 19435899
references.citation: Nat Med. 2002 Oct;8(10):1145-52
references.pmid: 12244301
references.citation: N Engl J Med. 2005 Dec 29;353(26):2747-57
references.pmid: 16382061
references.citation: J Natl Cancer Inst. 2005 Sep 7;97(17):1262-71
references.pmid: 16145047