Targeting both Notch and ErbB-2 signalling pathways is required for prevention of Erb

[Cathya]

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 Osipo^1,2,3,6,7

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