Cooperative blockade of FLT3 and ALK synergistically suppresses growth of osteosarcoma.

Osteosarcoma is a common primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors have emerged as potential treatments for osteosarcoma due to the critical role kinases play in regulating cellular networks. However, single-agent kinase inhibitors often face challenges due to the activation of compensatory oncogenic signaling pathways, which can undermine treatment efficacy. In this study, a combination screening of FDA-approved kinase inhibitors was conducted in osteosarcoma cells. We identified the combination of ALK inhibitor and FLT3 inhibitor as a potent kinase-based therapeutic strategy for osteosarcoma. Our results showed that the combinatorial treatment synergistically suppressed osteosarcoma in cell lines, patient-derived organoids, and xenograft models. Mechanistically, the inhibition of FLT3 significantly promoted the activation of ALK, which subsequently enhanced its downstream PI3K/Akt and MAPK signaling pathways. The combinatorial use of an ALK inhibitor could reverse this process. Thus, our study demonstrates that the cooperative blockade of FLT3 and ALK synergistically suppresses osteosarcoma, providing a potential alternative for its treatment.