The novel and selective insulin-like growth factor-1 receptor kinase inhibitor pqip suppresses bone cell function and osteoclast-breast cancer cell cross-talk

Breast cancers commonly metastasis to the bone microenvironment, disrupting the bone remodelling cycle causing predominantly osteolytic metastases. Insulin like growth factor 1 (IGF-1) is known to play functional roles in both bone cell and breast cancer cell biology. Here, we investigate the effects of PQIP, a novel, selective dual inhibitor of IGF-1 receptor (IGF-1R) and IR kinases, on bone cell differentiation, activity and interaction with breast cancer cell lines in vitro. Treatment of calvarial osteoblasts with PQIP resulted in a significant reduction in alkaline phosphatase activity (56%, p < 0.05), and bone nodule formation (40%, p < 0.05), in the presence and absence of IGF-1, without affecting cell viability. Moreover, PQIP suppressed IGF-1 induced migration of the osteoblast-like MC3T3-E1 cells (24%, p < 0.05) as measured by the wound healing assay. Interestingly, PQIP also inhibited RANKL production in osteoblasts (89%, p < 0.05), indicating a possible indirect inhibitory effect on osteoblast support for osteoclastagenesis. Studies in osteoclast cultures demonstrated that IGF-1 enhanced RANKL induced osteoclast formation (31%, p < 0.05), and that this effect was completely abolished by the presence of PQIP. Functional studies showed that PQIP treatment prevented IGF-1 induced AKT phosphorylation in osteoblast, osteoclast, and MDA-MB-231 cultures, confirming inhibition of IGF-1 receptor kinase signalling. Conditioned media from human MDA-MB-231, human MCF7, and mouse 4T1 breast cancer cells stimulated osteoclast formation in bone marrow cultures treated with RANKL and M-CSF, and this was significantly suppressed in the presence of PQIP (40–50% reduction, p < 0.05). Further mechanistic studies showed that PQIP also inhibited AKT phosphorylation in mature osteoclasts when induced by condition media from MDA-MB-231 cells, indicating an inhibitory effect on tumour cell support for osteoclastogenesis. In conclusion, the IGF-1R kinase inhibitor PQIP suppresses differentiation of bone cells and for the first time we showed that IGF-1R inhibition suppresses both osteoblast and breast cancer cell support for osteoclastogenesis in vitro. Therefore, derivatives of PQIP, which are now in advanced clinical development, may be of clinical value for the treatment of bone loss and metastases associated with breast cancer.