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GET THE INSIDE AND OUTSIDE STORY ON HER2 BLOCKADE

Understand the central role of HER2 in HER2+ MBC progression

Despite advances in HER2 targeting, HER2+ MBC almost invariably progresses.1 New approaches that selectively target HER2, from both inside and outside of the cell simultaneously, are needed to more comprehensively block HER2 signaling.2-4

Seattle Genetics: Advancing science to transform treatment of HER2+ cancer
EGFR = epidermal growth factor receptor; HER = human epidermal growth factor receptor; MAPK = mitogen-activated protein kinase; MBC = metastatic breast cancer; PI3K = phosphoinositide 3-kinase.
References: 1. Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471. 2. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol. 2012;30:2585-2592. 3. Rimawi MF, Wiechmann LS, Wang YC, et al. Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu-overexpressing breast tumor xenografts. Clin Cancer Res. 2011;17:1351-1361. 4. Ruiz-Saenz A, Moasser MM. Targeting HER2 by combination therapies. J Clin Oncol. 2018;36:808-811. 5. Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878-5887. 6. Pinkas-Kramarski R, Soussan L, Waterman H, et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J. 1996;15:2452-2467. 7. Hsieh AC, Moasser MM. Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer. 2007;97:453-457. 8. Arteaga CL, O’Neill A, Moulder SL, et al. A phase I-II study of combined blockade of the ErbB receptor network with trastuzumab and gefitinib in patients with HER2 (ErbB2)-overexpressing metastatic breast cancer. Clin Cancer Res. 2008;14:6277-6283. 9. Harandi A, Zaidi AS, Stocker AM, Laber DA. Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. J Oncol. 2009;2009:567486. 10. Jackson-Fisher AJ, Bellinger G, Shum E, et al. Formation of Neu/ErbB2-induced mammary tumors is unaffected by loss of ErbB4. Oncogene. 2006;25:5664-5672. 11. Li J. Diarrhea with HER2-targeted agents in cancer patients: a systematic review and meta-analysis. J Clin Pharmacol. 2019;59:935-946. 12. Garrett JT, Olivares MG, Rinehart C, et al. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci USA. 2011;108:5021-5026. 13. Sergina NV, Rausch M, Wang D, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437-444. 14. Luque-Cabal M, García-Teijido P, Fernández-Pérez Y, Sánchez-Lorenzo L, Palacio-Vázquez I. Mechanisms behind the resistance to trastuzumab in HER2-amplified breast cancer and strategies to overcome it. Clin Med Insights Oncol. 2016;10(Suppl 1):21-30. 15. Maruyama T, Mimura K, Izawa S, et al. Lapatinib enhances Herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER expression. Anticancer Res. 2011;31:2999-3005.