raionale for combined anti-her family treatment and hope for those primarily
 

resitant to herceptin, yet treated with herceptin--comes from experiments done so far in cell lines only

Cancer Res. 2009 Mar 10. [Epub ahead of print]
Trastuzumab-Induced HER Reprogramming in "Resistant" Breast Carcinoma Cells.

Narayan M, Wilken JA, Harris LN, Baron AT, Kimbler KD, Maihle NJ.
Division of Medical Oncology, Yale Cancer Center, Departments of Obstetrics, Gynecology, and Reproductive Sciences, Internal Medicine and School of Nursing, and Pathology and Pharmacology, Yale University, New Haven, Connecticut; and Department of Internal Medicine, Division of Hematology, Oncology, and Blood & Bone Marrow Transplantation, and Department of Epidemiology, University of Kentucky, Lexington, Kentucky.
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].
PMID: 19276389