Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic potential of the dual EGFR/HER2 inhibitor AZD8931 in circumventing endocrine resistance

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Modest up-regulation of either HER-ligands or receptors has been implicated in acquired endocrine resistance. AZD8931, a dual tyrosine kinase inhibitor (TKI) of epithelial growth factor receptor (EGFR)/HER2, has been shown to more effectively block ligand-dependent HER signaling than the HER TKIs lapatinib or gefitinib. We therefore examined the effect of AZD8931 in ER-positive/HER2-negative breast cancer cells with acquired resistance to tamoxifen, where there is ligand up-regulation associated with HER pathway activation. RNA-seq ligand profiling and levels of HER receptors and signaling by western blotting were conducted in ER+ MCF7 and T47D parental cells and their Tam-resistant derivatives (TamRes). In vitro cell growth and apoptosis and HER ligand-stimulated signaling were measured in response to endocrine and HER TKIs. For studies in vivo, transplantable MCF7/TamRes xenografts were treated with tamoxifen or fulvestrant, either alone or in combination with AZD8931. AZD8931 only minimally enhanced endocrine sensitivity in MCF7 parental cells, but showed a greater effect in the T47D parental model. AZD8931 combined with either tamoxifen or fulvestrant inhibited cell growth more than lapatinib in T47D TamRes cells, and was also significantly, though modestly, more potent in MCF7 TamRes cells. In both TamRes models, AZD8931 significantly inhibited cell proliferation and induced apoptosis. Under ligand-stimulated conditions, AZD8931 more potently inhibited HER signaling than lapatinib or gefitinib. AZD8931 also significantly delayed the growth of MCF7 TamRes xenografts in the presence of tamoxifen or fulvestrant. The strongest inhibition was achieved with a fulvestrant and AZD8931 combination, though no tumor regression was observed. This study provides evidence that AZD8931 has greater inhibitory efficacy in tamoxifen-resistant settings than in an endocrine therapy naïve setting. The absence of tumor regression, however, suggests that additional escape pathways contribute to resistant growth and will need to be targeted to fully circumvent tamoxifen resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Clark GM, Osborne CK, McGuire WL (1984) Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer. J Clin Oncol 2(10):1102–1109

    CAS  PubMed  Google Scholar 

  2. Osborne CK, Wakeling A, Nicholson RI (2004) Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer 90(Suppl 1):S2–S6

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Clark GM (1995) Prognostic and predictive factors for breast cancer. Breast Cancer 2(2):79–89

    Article  PubMed  Google Scholar 

  4. Osborne CK, Schiff R (2011) Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 62:233–247

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R (2008) Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 68(3):826–833

    Article  CAS  PubMed  Google Scholar 

  6. Drury SC, Detre S, Leary A, Salter J, Reis-Filho J, Barbashina V, Marchio C, Lopez-Knowles E, Ghazoui Z, Habben K et al (2011) Changes in breast cancer biomarkers in the IGF1R/PI3K pathway in recurrent breast cancer after tamoxifen treatment. Endocr Relat Cancer 18(5):565–577

    Article  CAS  PubMed  Google Scholar 

  7. Schiff R, Massarweh SA, Shou J, Bharwani L, Arpino G, Rimawi M, Osborne CK (2005) Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance: implicated role of growth factor signaling and estrogen receptor coregulators. Cancer Chemother Pharmacol 56(Suppl 1):10–20

    Article  PubMed  Google Scholar 

  8. Nicholson RI, Hutcheson IR, Britton D, Knowlden JM, Jones HE, Harper ME, Hiscox SE, Barrow D, Gee JM (2005) Growth factor signalling networks in breast cancer and resistance to endocrine agents: new therapeutic strategies. J Steroid Biochem Mol Biol 93(2–5):257–262

    Article  CAS  PubMed  Google Scholar 

  9. Gee JM, Robertson JF, Gutteridge E, Ellis IO, Pinder SE, Rubini M, Nicholson RI (2005) Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer. Endocr Relat Cancer 12(Suppl 1):S99–S111

    Article  CAS  PubMed  Google Scholar 

  10. Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, Wong J, Allred DC, Clark GM, Schiff R (2003) Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 95(5):353–361

    Article  CAS  PubMed  Google Scholar 

  11. de Mora Font (2000) J, Brown M: AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Mol Cell Biol 20(14):5041–5047

    Article  Google Scholar 

  12. Creighton CJ, Massarweh S, Huang S, Tsimelzon A, Hilsenbeck SG, Osborne CK, Shou J, Malorni L, Schiff R (2008) Development of resistance to targeted therapies transforms the clinically associated molecular profile subtype of breast tumor xenografts. Cancer Res 68(18):7493–7501

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137

    Article  CAS  PubMed  Google Scholar 

  14. Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, Seger R, Hynes NE, Yarden Y (1996) ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 15(2):254–264

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW (2003) Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 284(1):31–53

    Article  CAS  PubMed  Google Scholar 

  16. Yarden Y, Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12(8):553–563

    Article  CAS  PubMed  Google Scholar 

  17. Hynes NE, MacDonald G (2009) ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21(2):177–184

    Article  CAS  PubMed  Google Scholar 

  18. Dowsett M, Allred C, Knox J, Quinn E, Salter J, Wale C, Cuzick J, Houghton J, Williams N, Mallon E et al (2008) Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J Clin Oncol 26(7):1059–1065

    Article  CAS  PubMed  Google Scholar 

  19. Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell’Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Mery E, Lacroix-Triki M et al (2008) Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol 9(1):23–28

    Article  CAS  PubMed  Google Scholar 

  20. Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96(12):926–935

    Article  CAS  PubMed  Google Scholar 

  21. Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, Barrow D, Wakeling AE, Nicholson RI (2003) Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 144(3):1032–1044

    Article  CAS  PubMed  Google Scholar 

  22. Tang CK, Perez C, Grunt T, Waibel C, Cho C, Lupu R (1996) Involvement of heregulin-beta2 in the acquisition of the hormone-independent phenotype of breast cancer cells. Cancer Res 56(14):3350–3358

    CAS  PubMed  Google Scholar 

  23. Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin SK, Osborne CK (2004) Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res 10(1 Pt 2):331S–336S

    Article  CAS  Google Scholar 

  24. Johnston SR (2010) New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res 16(7):1979–1987

    Article  CAS  PubMed  Google Scholar 

  25. Cristofanilli M, Valero V, Mangalik A, Royce M, Rabinowitz I, Arena FP, Kroener JF, Curcio E, Watkins C, Bacus S et al (2010) Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. Clin Cancer Res 16(6):1904–1914

    Article  CAS  PubMed  Google Scholar 

  26. Osborne CK, Neven P, Dirix LY, Mackey JR, Robert J, Underhill C, Schiff R, Gutierrez C, Migliaccio I, Anagnostou VK et al (2011) Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer: a randomized phase II study. Clin Cancer Res 17(5):1147–1159

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Schwartzberg LS, Franco SX, Florance A, O’Rourke L, Maltzman J, Johnston S (2010) Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist 15(2):122–129

    Article  PubMed Central  PubMed  Google Scholar 

  28. Finn RS, Press MF, Dering J, O’Rourke L, Florance A, Ellis C, Martin AM, Johnston S (2014) Quantitative ER and PgR assessment as predictors of benefit from lapatinib in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res 20(3):736–743

    Google Scholar 

  29. Lupien M, Meyer CA, Bailey ST, Eeckhoute J, Cook J, Westerling T, Zhang X, Carroll JS, Rhodes DR, Liu XS et al (2010) Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance. Genes Dev 24(19):2219–2227

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Mayer IA, Arteaga CL (2010) Does lapatinib work against HER2-negative breast cancers? Clin Cancer Res 16(5):1355–1357

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. McDonagh CF, Huhalov A, Harms BD, Adams S, Paragas V, Oyama S, Zhang B, Luus L, Overland R, Nguyen S et al (2012) Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3. Mol Cancer Ther 11(3):582–593

    Article  CAS  PubMed  Google Scholar 

  32. Hickinson DM, Klinowska T, Speake G, Vincent J, Trigwell C, Anderton J, Beck S, Marshall G, Davenport S, Callis R et al (2010) AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer. Clin Cancer Res 16(4):1159–1169

    Article  CAS  PubMed  Google Scholar 

  33. Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, Botero MF, Healy NA, Hilsenbeck SG, Phillips GL et al (2011) Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers–role of estrogen receptor and HER2 reactivation. Breast Cancer Res 13(6):R121

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Osborne CK, Coronado E, Allred DC, Wiebe V, DeGregorio M (1991) Acquired tamoxifen resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. J Natl Cancer Inst 83(20):1477–1482

    Article  CAS  PubMed  Google Scholar 

  35. Emde A, Mahlknecht G, Maslak K, Ribba B, Sela M, Possinger K, Yarden Y (2011) Simultaneous inhibition of estrogen receptor and the HER2 pathway in breast cancer: effects of HER2 abundance. Transl Oncol 4(5):293–300

    PubMed Central  PubMed  Google Scholar 

  36. Britton DJ, Hutcheson IR, Knowlden JM, Barrow D, Giles M, McClelland RA, Gee JM, Nicholson RI (2006) Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res Treat 96(2):131–146

    Article  CAS  PubMed  Google Scholar 

  37. Johnston SR, Martin LA, Leary A, Head J, Dowsett M (2007) Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer. J Steroid Biochem Mol Biol 106(1–5):180–186

    Article  CAS  PubMed  Google Scholar 

  38. Osborne CK, Shou J, Massarweh S, Schiff R (2005) Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 11(2 Pt 2):865s–870s

    CAS  PubMed  Google Scholar 

  39. Leary AF, Drury S, Detre S, Pancholi S, Lykkesfeldt AE, Martin LA, Dowsett M, Johnston SR (2010) Lapatinib restores hormone sensitivity with differential effects on estrogen receptor signaling in cell models of human epidermal growth factor receptor 2-negative breast cancer with acquired endocrine resistance. Clin Cancer Res 16(5):1486–1497

    Article  CAS  PubMed  Google Scholar 

  40. Chu I, Blackwell K, Chen S, Slingerland J (2005) The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Cancer Res 65(1):18–25

    CAS  PubMed  Google Scholar 

  41. Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ et al (2009) Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 27(33):5538–5546

    Article  CAS  Google Scholar 

  42. Howell A, Osborne CK, Morris C, Wakeling AE (2000) ICI 182,780 (Faslodex): development of a novel, “pure” antiestrogen. Cancer 89(4):817–825

    Article  CAS  PubMed  Google Scholar 

  43. Kirkegaard T, Hansen SK, Larsen SL, Reiter BE, Sørensen BS, Lykkesfeldt AE (2014) T47D breast cancer cells switch from ER/HER to HER/c-Src signaling upon acquiring resistance to the antiestrogen fulvestrant. Cancer Lett 344(1):90–100

    Google Scholar 

  44. Gwin W, Liu L, Zhao S, Xia W, Spector N (2012) The impact of the heregulin-HER receptor signaling axis on response to HER tyrosine kinase inhibitors. Cancer Res 72(24Suppl):Abstract nr P4-08-03

  45. Hutcheson IR, Knowlden JM, Hiscox SE, Barrow D, Gee JM, Robertson JF, Ellis IO, Nicholson RI (2007) Heregulin beta1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells. Breast Cancer Res 9(4):R50

    Article  PubMed Central  PubMed  Google Scholar 

  46. Johnston SRD (2013) Phase II randomized study of the EGFR, HER2, HER3 signaling inhibitor AZD8931 in combination with anastrozole (A) in women with endocrine therapy (ET) naive advanced breast cancer (MINT). J Clin Oncol 31(suppl; abstr 531)

Download references

Acknowledgments

We thank T. Mitchell for assistance with the mouse studies and Dr. G. Chamness for discussing and reviewing this manuscript. This work was supported in part by the Dan L. Duncan Cancer Center Grant P30CA125123, the Breast Cancer Research Foundation (R. Schiff and C.K. Osborne), the AstraZeneca Research Grant, and Susan G. Komen for the Cure Foundation Promise Grant PG12221410.

Conflict of interest

R. Schiff, M. Rimawi, and C.K. Osborne have received research funding from AstraZeneca. T. Klinowska is an employee of AstraZeneca.

Author information

Authors and Affiliations

  1. Lester and Sue Smith Breast Center and Dan L Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, BCM:600, Houston, TX, 77030, USA

    Gladys Morrison, Xiaoyong Fu, Martin Shea, Sarmistha Nanda, Mario Giuliano, Tao Wang, C. Kent Osborne, Mothaffar F. Rimawi & Rachel Schiff

  2. Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, 77030, USA

    Gladys Morrison, C. Kent Osborne, Mothaffar F. Rimawi & Rachel Schiff

  3. Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA

    C. Kent Osborne, Mothaffar F. Rimawi & Rachel Schiff

  4. AstraZeneca Oncology iMed, Macclesfield, UK

    Teresa Klinowska

Authors
  1. Gladys Morrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoyong Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarmistha Nanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mario Giuliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Teresa Klinowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. Kent Osborne
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mothaffar F. Rimawi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rachel Schiff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rachel Schiff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morrison, G., Fu, X., Shea, M. et al. Therapeutic potential of the dual EGFR/HER2 inhibitor AZD8931 in circumventing endocrine resistance. Breast Cancer Res Treat 144, 263–272 (2014). https://doi.org/10.1007/s10549-014-2878-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-014-2878-x

Keywords

Search

Navigation