Based on these results, we and others have proposed that comprehensive analysis of expression of all four HER family members, and their isoforms, as well as key components of their sig selleck chemicals naling networks may be necessary to improve the positive predictive value of these theragnostic and prognostic bio marker assays. In this study we show that trastuzumab treatment results in the acquisition of de novo sensitivity to gefitinib or cetuximab in three of four EOC cell lines tested, imply ing that HER2 signaling Inhibitors,Modulators,Libraries is dispensable in these cells con comitant with compensatory EGFR signaling. While we note that HER2 expression was decreased in all three cell lines which acquired de novo drug sensitivity, the small number of cell lines used and single time point tested prevent us from concluding that HER2 downregulation is the mechanism of trastuzumab prim ing.

It is interesting to note, however, that complemen tary observations have been made in prostate cancer. gefitinib treatment of the prostate Inhibitors,Modulators,Libraries cancer cell line 22Rv1 sensitizes cells to the HER2 targeted antibody pertu zumab. Our study also further highlights the differences observed between breast Inhibitors,Modulators,Libraries and ovarian cancer responsive ness to trastuzumab. Such differences are perhaps not surprising given that the progenitors of mesodermally derived ovarian surface epithelial cells vs. ectodermally derived breast epithelial cells diverge early during embryonic gastrulation. It is, therefore, likely that the growth regulatory roles of HER2, as well as other HER family receptors, are divergent in these two tissues.

Such functional differences Inhibitors,Modulators,Libraries may be reflected in the empirical differences observed between these tumors, such as the higher frequency of Inhibitors,Modulators,Libraries HER2 gene amplification in breast vs. EOC tumors. In this context, while it is possible that long term trastuzumab treatment results in the selection of resistant ovarian cancer subclones, we favor the hypothesis that long term trastuzumab treatment may restrict generation to generation heritability of protein expression, a phenomenon recently described by Spencer et al. as a non genetic mechanism underlying tumor het erogeneity in response to targeted therapeutics. Moreover, a number of studies have demonstrated that in some HER2 positive breast carcinoma derived cell lines, trastuzumab treatment may not directly inhibit cell growth, but still results in latent but important pheno types. For selleck chemicals Vandetanib example, the HER2 positive breast cell line JIMT 1 in vitro and in xenograft models is not signifi cantly growth inhibited by trastuzumab, however, trastuzumab does inhibit establishment of distant metas tases.