Role of efflux pump activity in lapatinib/caelyx combination in breast cancer cell lines

The aim of this study was to investigate, at preclinical level, efflux pump modulation induced by lapatinib, a small-molecule dual inhibitor of the epidermal growth factor receptor (EGFR), in HER2-negative or HER2-positive breast cancer cell lines (SkBr3 and BRC230). We also evaluated the cytotoxic activity and modulation of biomolecular cellular pathways regulated by caelyx and lapatinib, used singly or in combination, at concentrations corresponding to peak plasma level in the two cell lines. Lapatinib was active in the HER2-overexpressing cell line, SkBr3, but not in BRC230 cell line, which does not express HER2. Conversely, caelyx exerted a cytotoxic effect on both the cell lines. Simultaneous exposure to lapatinib and caelyx in SkBr3 cell line produced an additive cytotoxic effect with dephosphorylation of HER2 and EGFR, an upregulation of p21, and an induction of apoptosis through dephosphorylation of BAD(Ser112) and caspase cleavage. In BRC230, simultaneous treatment induced a synergistic effect that was because of, at least in part, an upregulation of p21. Lapatinib also blocked efflux pumps, such as the breast cancer resistance protein I by increasing the length of time in which caelyx was present in tumor cell cytoplasm, which led to caspase cleavage, BAD(Ser112) dephosphorylation, and apoptosis, Our data indicate that lapatinib used in combination with caelyx is active in HER2-expressing cells, probably because of lapatinib-induced dephosphorylation of the HER2-EGFR pathway, and also in non-HER2-expressing cells, possibly because lapatinib blocks efflux pump activity, increasing the length of time of intracellular exposure to caelyx and thereby increasing its cytotoxic effect. Anti-Cancer Drugs 20:918-925 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.