In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 622-622
Kurzfassung:
622 Background: Although the HER2 gene is amplifiend/overexpressed in 15-20% of breast cancers, only a proportion of these patients benefit from anti-HER2 therapy. Clearly additional biomarkers and/or therapeutic targets are necessary to enhance efficacy and improve outcome in these patients. Here, we tested the hypothesis that inhibition of ADAM17-mediated release of HER ligands may enhance response to trastuzumab and lapatinib. Methods: The ADAM17-selective inhibitor, PF-5480090 (Pfizer) both alone and in combination with lapatinib, trastuzumab or 5FU was tested for potential growth inhibitory effects on a panel of 4 HER2-positive breast cancer cell lines (BT474, MDA-MB-453, SKBR3 and JIMT-1). Results: Using the MTT viability assay, treatment with 1 µM TMI-2 resulted in a significant reduction in cell proliferation compared to vehicle control in BT474 (p=0.01), MDA-MB-453 (p 〈 0.005), JIMT-1 (p=0.002) and SKBR3 cells (p 〈 0.005). Addition of PF-5480090 to lapatinib resulted in a significant reduction in cell growth compared to lapatinib alone (JIMT-1: p 〈 0.005; SKBR3: p 〈 0.005; MDA-MB-453: p 〈 0.005), while addition of PF-5480090 to trastuzumab resulted in significant reduction in cell growth compared to trastuzumab alone (JIMT-1: p 〈 0.005; SKBR3: p 〈 0.005; MDA-MB-453: p=0.001). Addition of PF-5480090 to 5FU resulted in significant reduction in growth compared to 5FU alone (JIMT-1: p 〈 0.005; SKBR3: p 〈 0.005; MDA-MB-453: p=0.001). Consistent with its ability to block proliferation, addition of PF-5480090 significantly reduced release of TGFalpha (BT474: p=0.003; JIMT1: p=0.023; SKBR3: p=0.036 and MDA-MB-453: p=0.014). Conclusions: Inhibitionof ADAM17 resulted in growth inhibitory responses in HER2-positive breast cancer cell lines. Furthermore, addition of PF-5480090 to lapatinib, trastuzumab or 5FU resulted in significant growth inhibition compared to these agents alone. We propose that inhibition of ADAM17 may be used in combination with existing treatments for HER2-positive breast cancer. Acknowledgement. The authors thank SFI (SRC award, 08/SRC/B1410 to MTCI) for funding this work.
Materialart:
Online-Ressource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.622
Sprache:
Englisch
Verlag:
American Society of Clinical Oncology (ASCO)
Publikationsdatum:
2012
ZDB Id:
2005181-5
