An allosteric SHP2 inhibitor suppresses breast cancer-induced osteoclastogenesis and bone lysis

Inhibition of osteoclast hyperactivation represents a promising therapeutic approach for pathological bone destruction induced by breast cancer bone metastasis. Inhibitors of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 2 (SHP2), a protein tyrosine phosphatase (PTP) oncoprotein, show prominent antitumour activity, and eight allosteric inhibitors among them have entered clinical trials. However, the role of SHP2 in tumour-associated osteoclastogenesis remains unexplored. This study observed that SHP2 expression was increased in bone tissue with breast cancer cell metastasis. It further demonstrates that SHP099, an allosteric inhibitor of SHP2, suppresses human breast cancer MDA-MB-231 cell conditioned medium (CM)-induced osteoclast differentiation and bone resorption from 250 nM in vitro. Notably, SHP099 disrupts F-actin rings formation and downregulates osteoclast-specific genes. Mechanistically, SHP099 inhibits the phosphorylation of p38 mitogen-activated protein kinases (MAPK), c-Fos and calcium oscillation downstream of SHP2, thereby suppressing Nuclear Factor of Activated T-cells, Cytoplasmic 1 (NFATc1) nuclear translocation. In a murine model of MDA-MB-231-induced osteolytic lesions, oral administration of 10 mg/kg SHP099 reduces osteoclasts and prevents the trabecular bone loss. Our study identifies SHP2 as a druggable target for inhibiting breast cancer-induced osteoclast differentiation, positioning the specific inhibitors of SHP2 as potential drugs developed to treat tumour-induced osteolysis in the future.