Abstract P2-05-26: Focal adhesion kinase is required for efficient tumor-induced osteoclastogenesis via control of macrophage colony stimulating factor expression

Abstract

Abstract Breast cancer most commonly metastasizes to bone where metastases cause the potentiation of the vicious cycle. During this process, breast cancer bone metastases inhibit osteoblasts from forming new bone, while also activating osteoclasts to degrade bone. This in turn causes release of bone-matrix bound growth factors which propagate tumor growth. The overall net bone destruction can lead to significant adverse clinical consequences for patients including fractures or substantial pain. While agents such as bisphosphonates or the monoclonal antibody to RANKL denosumab, both of which inhibit the osteolytic activity of osteoclasts, are currently used in breast cancer bone metastatic patients to alleviate these adverse clinical outcomes, they have not been associated with increased patient survival. Given the lack of successful treatments for bone metastases providing survival advantages, we sought to evaluate the role of focal adhesion kinase (FAK), a novel therapeutic target, in breast cancer mediated osteolysis. FAK is a non-receptor tyrosine kinase that regulates many pathways that contribute to enhanced tumor progression and metastasis. FAK is also expressed in all the cell types involved in the vicious cycle. We thus hypothesized that FAK plays an important role in breast tumor-induced osteolysis and that its inhibition would lead to restoration of bone homeostasis, in addition to inhibition of tumor progression. Using in vitro siRNA-targeted depletion of FAK in breast cancer tumor cell lines, we found that production of numerous soluble growth factors, many of which are known contributors to osteoclastogenesis, was inhibited. We confirmed that FAK regulates the expression of the osteoclastogenic factor macrophage colony stimulating factor in breast cancer cell lines. Further, using conditioned media from FAK expressing versus depleted breast cancer tumor cells in osteoclastogenesis assays, we show that FAK-depletion results in impaired osteoclastogenesis. These data suggest that in addition to its proven direct anti-tumor effects, inhibition of FAK may also result in therapeutic blockade of bone degradation. Citation Format: Landon K, Howe GA, Zhao H, Addison CL. Focal adhesion kinase is required for efficient tumor-induced osteoclastogenesis via control of macrophage colony stimulating factor expression. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-26.