Abstract #4713: Salvaging trastuzumab as an ovarian cancer therapeutic: Augmentation of EGFR-targeted therapeutics with trastuzumab

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Introduction: Trastuzumab, a therapeutic antibody that targets ErbB2, has proven to be exceptionally useful as a treatment for ErbB2-positive breast cancer. In contrast, however, trastuzumab has been shown to be ineffective as a treatment option for ovarian cancer, despite the observation that a similar proportion of ovarian and breast tumors are ErbB2-positive. Consequently, trastuzumab has quickly lost favor as an experimental therapeutic for the treatment of ovarian cancer. Given the response rate of trastuzumab in both early and late stage breast cancer patients, surprisingly little attention has been given to either the basis for the apparent primary resistance of ErbB2-positive ovarian tumors to trastuzumab, or to ways of perhaps salvaging Herceptin as an experimental ovarian cancer therapeutic. Our in vitro studies suggest that this biologically-targeted therapeutic may still hold potential in ovarian cancer patients. Methods: Ovarian carcinoma-derived cell lines expressing high (OVCAR-7 and SKOV-3) or moderate (A1847 and IGROV-1) levels of ErbB2 were cultured for 12 weeks in the presence (T100) or absence (parental) of 100 \#956;g/ml trastuzumab. After 12 weeks, parental vs. T100 ErbB receptor expression patterns were analyzed by immunoblot of cell lysates. Based on these results, response to several FDA-approved EGFR-targeted therapeutics including gefitinib and cetuximab was evaluated. Results: Both ErbB receptor expression levels and proliferative response to ligand changed dramatically in response to continuous long-term exposure of ovarian cancer cells to trastuzumab. Ovarian carcinoma-derived cells are therefore not \#8220;unresponsive\#8221; to trastuzumab as previously assumed, but rather, trastuzumab effects alternate ErbB expression and function. Moreover, this reprogramming of ErbB expression and function resulted in three of four T100 vs. parental cell lines acquiring de novo sensitivity to EGFR-targeted therapeutics (p<0.05): A1847 T100 cells became growth inhibited by cetuximab, OVCAR-7 T100 cells became growth inhibited by gefitinib, and IGROV-1 T100 cells became growth inhibited by both gefitinib and cetuximab. Conclusions: Long-term trastuzumab treatment of ErbB2-positive ovarian carcinoma-derived cell lines results in a functional reprogramming of the ErbB tyrosine kinase receptor axis. Here, we provide in vitro evidence that ovarian cancer cells may be \#8220;primed\#8221; by long-term trastuzumab treatment to become sensitive to EGFR-targeted therapeutics such as gefitinib and cetuximab. We propose that with the recent success of clinical trials on EGFR-targeted therapeutics against other solid tumors, and also given the well-established safety profile of trastuzumab, these results provide the rationale for re-evaluation of trastuzumab as an experimental ovarian cancer therapeutic, either in concert with or as a \#8220;primer\#8221; for EGFR-targeted drugs. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4713.