[HTML][HTML] Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence
K Pandya, K Meeke, AG Clementz, A Rogowski… - British journal of …, 2011 - nature.com
K Pandya, K Meeke, AG Clementz, A Rogowski, J Roberts, L Miele, KS Albain, C Osipo
British journal of cancer, 2011•nature.comBackground: 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 …
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 …
Abstract
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.
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