Inhibition of IGFBP-3 signaling through sphingosine kinase-1 sensitizes triple-negative breast cancer cells to EGFR blockade — The Association Specialists
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Inhibition of IGFBP-3 signaling through sphingosine kinase-1 sensitizes triple-negative breast cancer cells to EGFR blockade (400)

Hasanthi C De Silva 1 , Carolyn D Scott 1 , Robert C Baxter 1 , Janet L Martin 1
  1. Kolling Institute, St Leonards, NSW, Australia

Background: Insulin like growth factor binding protein-3 (IGFBP-3) and epidermal growth factor receptor (EGFR) are highly expressed in triple-negative breast cancers (TNBC), an aggressive form of cancer that is difficult to treat using conventional therapies as they lack estrogen and progesterone receptors and HER2. Previously we have shown that IGFBP-3 enhances signaling through EGFR and stimulates the growth of breast epithelial cells by activating sphingosine kinase 1 (SphK1) and stimulating production of sphingosine 1-phosphate (S1P), which is implicated in progression and chemoresistance of breast cancer.

Aims: To investigate through in vitro and in vivo studies, whether co-targetting EGFR and SphK1/S1P in TNBCs may have greater efficacy than blocking either pathway alone.

Methods: TNBC cells were treated with gefitinib (EGFR inhibitor) and/or SKI-II (SphK1 inhibitor) prior to measuring cell proliferation by real-time imaging using IncuCyte. For in vivo studies, gefitinib and/or SKi-II were administered i.p. 3 times weekly into nude mice bearing MDA-MB-468 tumours. To elucidate the mechanism of growth inhibition, phosphorylation of signalling intermediates and cell cycle proteins, as well as cleavage of PARP as a marker of apoptosis, were measured in treated cells and excised tumours by western blot.

Results: Cell proliferation studies revealed a synergistic inhibitory effect of gefitinib and SKi-II in all cell lines. In vivo, the two inhibitors alone had no significant effect on tumour weight or volume compared with vehicle control, but the combination of SKi-II and gefitinib significantly reduced both parameters. Preliminary data suggest that the combined effect of gefitinib and SKi-II involves modulation of specific pathways in different TNBC cell lines.

Conclusion: Agents targetting EGFR and SphK/S1P show a synergistic inhibitory effect on TNBC cell proliferation and tumour growth in vivo, suggesting that this treatment combination may have therapeutic potential.

Supported by the NSW Cancer Council and a private donation.