Cathya
09-07-2011, 05:41 PM
Translational Therapeutics
British Journal of Cancer (2011) 105, 796–806. doi:10.1038/bjc.2011.321 www.bjcancer.com (http://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 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff1)</sup>, K Meeke<sup>2 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff2)</sup>, A G Clementz<sup>3 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff3)</sup>, A Rogowski<sup>1 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff1)</sup>, J Roberts<sup>2 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff2)</sup>, L Miele<sup>4 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff4)</sup>, K S Albain<sup>5 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff5)</sup> and C Osipo<sup>1 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff1),2 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff2),3 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff3),6 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff6),7 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff7)</sup>
<sup>1</sup>Molecular Biology Program, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
<sup>2</sup>Oncology Institute, Stritch School of Medicine at Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA
<sup>3</sup>Molecular and Cellular Biochemistry Program, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
<sup>4</sup>University of Mississippi Cancer Institute, 350 Woodrow Wilson Drive, Suite 600, Jackson, MS 39213, USA
<sup>5</sup>Department of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
<sup>6</sup>Department of Pathology, 2160 South First Avenue, Maywood, IL 60153, USA
<sup>7</sup>Department 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 page (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#top)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.
Keywords:
ErbB-2; trastuzumab; Notch-1; GSI; recurrence; resistance
British Journal of Cancer (2011) 105, 796–806. doi:10.1038/bjc.2011.321 www.bjcancer.com (http://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 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff1)</sup>, K Meeke<sup>2 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff2)</sup>, A G Clementz<sup>3 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff3)</sup>, A Rogowski<sup>1 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff1)</sup>, J Roberts<sup>2 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff2)</sup>, L Miele<sup>4 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff4)</sup>, K S Albain<sup>5 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff5)</sup> and C Osipo<sup>1 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff1),2 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff2),3 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff3),6 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff6),7 (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#aff7)</sup>
<sup>1</sup>Molecular Biology Program, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
<sup>2</sup>Oncology Institute, Stritch School of Medicine at Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA
<sup>3</sup>Molecular and Cellular Biochemistry Program, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
<sup>4</sup>University of Mississippi Cancer Institute, 350 Woodrow Wilson Drive, Suite 600, Jackson, MS 39213, USA
<sup>5</sup>Department of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
<sup>6</sup>Department of Pathology, 2160 South First Avenue, Maywood, IL 60153, USA
<sup>7</sup>Department 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 page (http://www.nature.com/bjc/journal/v105/n6/abs/bjc2011321a.html?WT.ec_id=BJC-201109#top)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.
Keywords:
ErbB-2; trastuzumab; Notch-1; GSI; recurrence; resistance