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Trastuzumab-Induced HER Reprogramming in "Resistant" Breast Carcinoma Cells

¹ Division of Medical Oncology, Yale Cancer Center, Departments of ² Obstetrics, Gynecology, and Reproductive Sciences, ³ Internal Medicine and School of Nursing, and ⁴ Pathology and Pharmacology, Yale University, New Haven, Connecticut; and ⁵ Department of Internal Medicine, Division of Hematology, Oncology, and Blood & Bone Marrow Transplantation, and ⁶ Department of Epidemiology, University of Kentucky, Lexington, Kentucky

Requests for reprints: Nita J. Maihle, 300 George Street, Suite 770, New Haven, CT 06511. Phone: 203-737-1385; Fax: 203-737-2914; E-mail: nita.maihle{at}yale.edu.

Key Words: HER/ErbB • primary resistance • trastuzumab

Although trastuzumab (Herceptin) is an important advance in the treatment of breast cancer, a significant proportion of patients do not respond to trastuzumab either alone or in combination with chemotherapy. In this study, we observe that epidermal growth factor receptor (EGFR) and HER3 expression is substantially increased after long-term trastuzumab exposure of HER2-positive breast carcinoma–derived cell lines that show primary resistance to trastuzumab. Furthermore, long-term trastuzumab exposure of trastuzumab-resistant cell lines induces de novo sensitivity to the EGFR-targeted agents gefitinib or cetuximab in two of three cell lines accompanied by increased EGFR expression. Together, these results indicate that primary trastuzumab resistance is not synonymous with lack of responsiveness to trastuzumab and, importantly, suggest that trastuzumab priming may sensitize trastuzumab-resistant tumors to other HER family-directed therapeutics. [Cancer Res 2009;69(6):2191–4]