An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti-IL-6 antibody-induced apoptosis Short title: Inhibitor of EGF receptor family in myeloma

We previously found that some myeloma cell lines express the heparin-binding epidermal growth factor-like growth factor (HB-EGF) gene. As the proteoglycan syndecan-1 is an HB-EGF coreceptor as well as a hallmark of plasma cell differentiation and a marker of myeloma cells, we studied the role of HB-EGF on myeloma cell growth. The HB-EGF gene was expressed by bone marrow mononuclear cells of 8/8 patients with myeloma, particularly by monocytes and stromal cells, but not by purified primary myeloma cells. 6/9 myeloma cell lines and 9/9 purified primary myeloma cells expressed ErbB1 or ErbB4 genes coding for HB-EGF receptor. In the presence of a low IL-6 concentration, HB-EGF stimulated the proliferation of the six ErbB1 or ErbB4 cell lines, through the PI-3K/AKT pathway. A pan-ErbB inhibitor blocked the myeloma cell growth factor activity and the signaling induced by HB-EGF. This inhibitor induced apoptosis of patients' myeloma cells cultured with their tumor environment. It also increased patients’ myeloma cell apoptosis induced by an anti-IL6 antibody or dexamethasone. The ErbB inhibitor had no effect on the interaction between MM cells and stromal cells. It was not toxic for non-myeloma cells present in patients’ bone marrow cultures or for the growth of hematopoietic progenitors. Altogether, these data identify ErbB receptors as putative therapeutic targets in multiple myeloma. [email protected] For personal use only. on November 16, 2017. by guest www.bloodjournal.org From