AVIL promotes osteosarcoma progression and cisplatin resistance via ARP2/3-mediated DNA damage repair

Osteosarcoma (OS) is the most common primary malignant tumor of bone that commonly occurs in adolescents with poor prognosis. Neoadjuvant chemotherapy with the MAP regimen (high-dose methotrexate (Methotrexate), doxorubicin, and cisplatin) is essential for the standardized OS therapeutic, the good response of which critically exceeds the patient survival. However, approximately 30-40 % of patients develop chemoresistance, leading to metastatic disease or recurrence. Understanding the molecular mechanisms underlying chemoresistance is crucial for improving clinical outcomes. In this study, AVIL was identified as a key gene correlated with OS progression and chemoresistance. AVIL overexpression was found to promote OS progression in vitro and in vivo by enhancing cell proliferation, migration, and invasion, while AVIL deficiency exerted the inverse phenotypes. In vivo experiments further confirmed that AVIL overexpression promotes tumor growth and suppresses apoptosis. Mechanistically, AVIL interacts with the ARP2/3 complex, a key regulator of DNA damage repair via actin polymerization and cytoskeletal dynamics. This interaction was confirmed to facilitate cisplatin resistance, with reduced DNA damage response and increased cell survival caused by AVIL overexpression. Furthermore, using patient-derived organoid (PDO) models, we demonstrated that CK666, an ARP2/3 inhibitor, enhanced the chemotherapy efficacy of cisplatin by increasing DNA damage response and reversing AVIL-mediated cisplatin resistance. These findings highlight AVIL as a potential therapeutic target and suggest that targeting the AVIL-ARP2/3 axis could serve as an alternative strategy to overcome chemoresistance during OS treatment.