Targeting inhibitor of apoptosis proteins in combination with ErbB antagonists in breast cancer
Foster FM et al. - In a study to examine the levels of inhibitor of apoptosis (IAPs) in breast cancer and evaluate whether targeting IAPs can enhance apoptosis in response to growth factor receptor antagonists and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), it was shown that multiple IAPs are concomitantly expressed in breast cancers, and that, in combination with clinically relevant Her2 treatments, IAP antagonists promote apoptosis and reduce the cell turnover index of breast cancers. Combination therapy of IAP antagonists with some pro-apoptotic agents enhances apoptosis of breast cancer cells. Methods- IAP levels were examined in a breast cancer cell line panel and in pt samples.
- IAPs were inhibited using siRNA or cell permeable mimetics of endogenous inhibitors.
- Cells were then exposed to TRAIL, Trastuzumab, Lapatinib, or Gefitinib for 48 hrs.
- Examining nuclear morphology and staining for cleaved caspase 3 was used to score apoptosis.
- Proliferation was examined by Ki67 staining.
Results- 4 members of the IAP family, Survivin, XIAP, cIAP1 and cIAP2, were all expressed to varying extents in breast cancer cell lines or tumours.
- MDAMB468, BT474, and BT20 cells all expressed XIAP to varying extents.
- Depleting the cells of XIAP overcame the intrinsic resistance of BT20 and MDAMB468 cells to TRAIL.
- siRNA based depletion of XIAP, or use of a Smac mimetic to target multiple IAPs, increased apoptosis in response to the ErbB antagonists, trastuzumab, lapatinib, or gefitinib in Her2-overexpressing BT474 cells, or gefitinib in EGFR-overexpressing MDAMB468 cells.
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