Inhibition of SRC prevents bone metastasis of breast cancer by blocking metastatic cell motility and bone directionality.

Rationale: Breast cancer bone metastasis remains a major cause of mortality with limited effective therapies. Although SRC is one of the earliest identified oncogenic kinases and has been extensively studied as a regulator of cancer progression and migration, it has not yet been successfully translated into an effective therapeutic target in solid tumors, highlighting the need to redefine SRC-targeted strategies in this context. Methods: Genetic deletion and pharmacological approaches were employed to interrogate SRC function, including comparative evaluation of conventional kinase inhibitors and next-generation inhibitors targeting both kinase and scaffolding functions. Cytoskeletal remodeling and cell motility were assessed via F-actin organization and focal adhesion signaling. Preclinical bone metastasis models were used to assess the extent of bone metastasis. Therapeutic efficacy was evaluated under both monotherapy and combination regimens with gemcitabine/bisphosphonate or anti-PD-1. Results: SRC phosphorylation regulated the activation of cytoskeletal regulators FAK and paxillin, thereby controlling cancer cell motility. Genetic deletion or pharmacological inhibition of SRC significantly suppressed cell motility, reduced F-actin remodeling, increased bone density, and inhibited bone metastasis Conclusions: This study demonstrates that SRC plays distinct and essential roles in cancer cell motility, osteoclast activation, and immune evasion, which collectively drive breast cancer bone metastasis. These findings establish SRC as a critical therapeutic target and suggest that dual inhibition of its kinase and scaffolding functions represents a more effective strategy than conventional approaches.