Multiple myeloma is still incurable. Myeloma cells become resistant to common drugs and patients eventually die of tumour progression. Therefore, new targets and drugs are needed immediately.
NVP-AEW541 is a new, orally bioavailable small molecule inhibitor of the
insulin-like growth factor-1 receptor (IGF-1R). Here, we show that
NVP-AEW541 inhibits cell growth in myeloma cells at low concentrations in a time-dependent and a dose-dependent manner. Further experiments using the
annexin-V-
fluorescein isothiocyanate/
propidium iodide assay revealed induction of apoptosis in common myeloma cell lines, but not in peripheral blood mononuclear cell from healthy donors. Stimulation of myeloma cells with
IGF-1 led to a vast increase of cell growth and this was blocked by low doses of
NVP-AEW541. Stimulation of myeloma cells with
conditioned medium obtained from a 48-h-old HS-5 stromal cell culture was only partly blocked by
NVP-AEW541. Western blotting experiments revealed that
NVP-AEW541 decreased the phosphorylation status of P70S6
kinase and 4E-BP-1 but not of
mammalian target of rapamycin (mTOR). Combined inhibition of IGF-1R and mTOR using the novel mTOR inhibitor
Rad001 led to additive/synergistic increase of cell growth inhibition in
multiple myeloma cells, which was accompanied by a stronger dephosphorylation of P70S6
kinase and 4E-BP-1. Taken together, we show that the combined inhibition of IGF-1R and mTOR by combining
NVP-AEW541 and
Rad001 is highly effective in
multiple myeloma and might represent a potential new treatment strategy.