Abstract 522: One drug- Two targets in osteosarcoma

Osteosarcoma, the most common primary malignant bone tumor, mostly affects adolescents and older adults, with limited therapeutic advances leading to poor survival rates for metastatic or recurrent cases. Current treatments often fail due to high mutational burdens and chemoresistance, necessitating new targeted therapies. In this study, we investigated the potential of PCT, a kinase inhibitor recently approved for hematological malignancies, for its anticancer effect against osteosarcoma. Our comprehensive in vitro analysis demonstrated that PCT inhibits cell viability, induces apoptosis, and causes G2/M arrest in multiple osteosarcoma cells. Gene expression analysis indicated that at very low micromolar concentrations, PCT inhibits the expression of AXL, β-Catenin and key players of the pathway at protein and mRNA level. Molecular docking analysis indicated PCT’s high binding affinity to AXL confirming our observations that PCT suppresses AXL/β-Catenin expression and transcriptional activity. Oral administration of PCT significantly reduced osteosarcoma tumor growth in murine models without any observable toxicity. The tumors of PCT treated mice exhibited inhibition of AXL and β-Catenin signalling axis and induction of apoptosis. Our findings suggest PCT as a dual inhibitor of AXL and β-catenin, directly affecting osteosarcoma progression. This research highlights PCT’s potential as a targeted therapeutic for osteosarcoma, offering new avenues to improve outcomes for patients with this aggressive malignancy. Citation Format: Marina Curcic, Sanjay K. Srivastava. One drug- Two targets in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 522.