http://erc.endocrinology-journals.org/cgi/...t/full/11/4/623
"There are also now several reports that logical combination of anti-hormonal and various anti-growth-factor strategies (e.g. anti-HER2, EGFR or Ras signaling) may be particularly powerful in preventing emergence of resistance, as well as restoring anti-hormone responsiveness in resistant cells (Wakeling et al. 2001, Johnston et al. 2003, Jones et al. 2004). Our own studies have demonstrated that when gefitinib is administered to anti-hormone-sensitive cells in combination with tamoxifen or fulvestrant (in anticipation of the development of EGFR signaling as a resistance mechanism), combination treatment promotes a much improved anti-proliferative and apoptotic effect than achieved with either drug alone (Gee et al. 2003, Nicholson et al. 2004). Indeed, apoptosis is so high using combination therapy that total cell kill is achieved and development of anti-hormone resistance is prevented (Gee et al. 2003). We hypothesize that since anti-hormones induce EGFR expression, early signaling from this receptor stimulates a survival pathway which reduces anti-hormone-mediated cell kill. Thus, the anti-hormone-treated cells, although initially growth inhibited, survive and eventually establish a resistant state driven by the EGFR pathway, an event abrogated by co-treatment with gefitinib (Gee et al. 2003). In a similar manner, we have recently described that co-targeting of EGFR and IGF-1R in our acquired tamoxifen-resistant cells is superior to inhibition of either pathway alone, where IGF-1R signaling clearly forms the survival and resistance mechanism recruited during treatment with gefitinib alone (Nicholson et al. 2004). Moreover, combination studies from Massarweh et al. (2002) have demonstrated that gefitinib delays resistance to estrogen deprivation and improves tamoxifen’s anti-tumor activity in their de novo tamoxifen-resistant HER-2 transfected MCF-7 cells. "
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