ER ER ER ER - Endocrine Reviews

een used in hopes of preventing resistance and improving therapeutic efficacy of
endocrine agents (83).
In vitro, the combination of tamoxifen and the selective EGFR TKI gefitinib, provided
nearly complete inhibition of p42/44 MAPK and AKT phosphorylation, greater
suppression of the cell-survival protein Bcl-2, and more complete G0/G1 cell-cycle arrest
than that observed with tamoxifen alone (97). In particular, this combined therapy
prevented acquired EGFR/p42/44 MAPK signaling and significantly delayed the
subsequent resistance that started to develop after 5 weeks in tamoxifen-alone-treated
cells. For de novo tamoxifen resistant breast cancer models made by stable transfection of
HER2, the strategy of combining endocrine therapy with different HER inhibitors or
other STIs is also more effective than using either therapy alone (14, 154, 157). A
synergistic effect has also been reported for the antiHER2 antibody trastuzumab
combined with tamoxifen in ER-positive, endogenously HER2-positive BT474 breast
cancer cells, with enhanced accumulation of cells in G0/G1 and a reduction in S-phase
compared with either therapy alone (161). Recently, the dual EGFR/HER2 TKI lapatinib
(Tykerb, GW57016) has been shown to cooperate with tamoxifen and other endocrine
agents to provide more rapid and profound cell-cycle arrest than either therapy alone in
endocrine-resistant cells (162, 163).
In vivo, it has been shown that gefitinib added to tamoxifen can completely overcome the
agonist activity of tamoxifen and significantly delay the growth of stably transfected
HER2-positive MCF-7 xenografts (14). Similar beneficial effects were seen with
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