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Translational Therapeutics

British Journal of Cancer (2011) 105, 796–806. doi:10.1038/bjc.2011.321 www.bjcancer.com
Published online 16 August 2011
Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence

K Pandya1, K Meeke2, A G Clementz3, A Rogowski1, J Roberts2, L Miele4, K S Albain5 and C Osipo1,2,3,6,7

1Molecular Biology Program, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
2Oncology Institute, Stritch School of Medicine at Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA
3Molecular and Cellular Biochemistry Program, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
4University of Mississippi Cancer Institute, 350 Woodrow Wilson Drive, Suite 600, Jackson, MS 39213, USA
5Department of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
6Department of Pathology, 2160 South First Avenue, Maywood, IL 60153, USA
7Department of Microbiology and Immunology, 2160 South First Avenue, Maywood, IL 60153, USA

Correspondence: Dr C Osipo, E-mail: cosipo@lumc.edu
Received 9 May 2011; Revised 12 July 2011; Accepted 18 July 2011; Published online 16 August 2011.

Top of pageAbstract

Background:

We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer.

Methods:

We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo.

Results:

Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours.

Conclusion:

Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.

Keywords:

ErbB-2; trastuzumab; Notch-1; GSI; recurrence; resistance