Kinase Inhibitors Screen Tamoxifen Resistant Breast Cancer

Antiestrogen resistance of breast cancer has been related to enhanced growth factor receptor expression and activation. We have previously shown that ectopic expression and subsequent activation of the insulin-like growth factor-1 receptor (IGF1R) or the epidermal growth factor receptor (EGFR) in MCF7 or T47D breast cancer cells results in antiestrogen resistance. In order to identify critical therapeutic targets that mediate this antiestrogen resistance, we performed a kinase inhibitor screen with 273 different inhibitors. Various ALK inhibitors, including TEA684, AZD3463 and LDK378, inhibited cell proliferation in IGF1R expressing cells under both normal and antiestrogen resistance conditions by preventing IGF1R activation and subsequent downstream signaling; ALK inhibitors did not affect EGFR signaling. On the other hand, MEK1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. The MEK inhibitors PD0325901, selumetinib, trametinib and TAK733 caused an arrest in the G0/G1 cell cycle phase only under antiestrogen resistance conditions in IGF1R expressing cells, but not under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. In a group of 291 patients with primary operable ER+ breast cancer, strong pMEK staining in metastatic breast cancer after first-line tamoxifen treatment was significantly related to no clinical benefit. We propose a critical role for MEK activation in IGF1R signaling-mediated antiestrogen resistance and anticipate that dual-targeted therapy with MEK inhibitor and antiestrogen could improve treatment outcome.