Targeting both Notch and ErbB-2 signalling pathways is required for prevention of Erb
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 Pandya<sup>1</sup>, K Meeke<sup>2</sup>, A G Clementz<sup>3</sup>, A Rogowski<sup>1</sup>, J Roberts<sup>2</sup>, L Miele<sup>4</sup>, K S Albain<sup>5</sup> and C Osipo<sup>1,2,3,6,7</sup>
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 |
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