Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence

• Published in: British journal of cancer Vol. 105; no. 6; pp. 796 - 806
• Main Authors: PANDYA, K, MEEKE, K, CLEMENTZ, A. G, ROGOWSKI, A, ROBERTS, J, MIELE, L, ALBAIN, K. S, OSIPO, C
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 06.09.2011
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - therapeutic use; Animals; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Breast Neoplasms - prevention & control; Cancer research; Cancer therapies; Cell Line, Tumor; Cyclic S-Oxides - pharmacology; Cytotoxicity; Drug Resistance, Neoplasm; Epidermal growth factor; Female; Gene amplification; Gene Targeting; Genes, erbB; Genes, erbB-2; Gynecology. Andrology. Obstetrics; Humans; Kinases; Lapatinib; Ligands; Mammary gland diseases; Medical prognosis; Medical research; Medical sciences; Metastasis; Mice; Mice, Nude; Neoplasm Transplantation; Quinazolines - administration & dosage; Receptor, ErbB-2 - metabolism; Receptors, Notch - antagonists & inhibitors; Receptors, Notch - genetics; Recurrence; Signal Transduction - drug effects; Thiadiazoles - pharmacology; Translational Therapeutics; Trastuzumab; Tumors; Womens health; United States > US; Antineoplastic agent; ErbB-2; Relapse; Notch receptor; Breast disease; Targeting; Breast tumor; erbB2 Gene; Monoclonal antibody; Prevention; Resistance; recurrence; Mammary gland diseases; Cancerology; Signaling pathway; Notch-I; C-Onc gene; GSI; Protooncogene; Trastuzumab
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.321

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. 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. 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. 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.