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Enhanced combination treatment on osteosarcoma by mitigating drug-induced oncogenic signaling pathway activation

ABSTRACT: Osteosarcoma is a prevalent primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors emerged as potential treatment for osteosarcoma due to the critical role of kinases regulating network. 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 systematic combination screening of kinase inhibitors was further conducted in osteosarcoma cells. Among 190 pair-wise combinations, 44 exhibited strong synergistic antitumor efficacy. Notably, the combination of the ALK inhibitor Ceritinib and the FLT3 inhibitor Crenolanib showed significant synergistic effects against osteosarcoma cell lines, patient-derived organoids in vitro, and xenograft models in vivo. This combination also effectively mitigated the compensatory activation of oncogenic signaling pathways, a common resistance mechanism to single-agent therapies. Our findings provide compelling evidence that dual kinase inhibition targeting ALK and FLT3 can effectively exploit pharmacological vulnerabilities in osteosarcoma, suggesting a promising therapeutic strategy for clinical application. This combinatorial approach could potentially overcome the limitations of single-agent therapies and improve outcomes for patients with osteosarcoma. Further clinical evaluation is warranted to confirm these preclinical results.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278302 | GEO | 2024/10/29

REPOSITORIES: GEO

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Project description:Abnormalities in the FLT3 signaling pathway play an integral role in AML disease relapse and drug resistance. Developing new and specific FLT3 tyrosine kinase inhibitors for use in combination to induction therapy is an important step to reduce disease relapse and achieve clinical remission. To develop potent FLT3 TKI requires sensitive in vitro assay that depended on efficient FLT3 artificial substrates, which there are none reported for FLT3 WT and kinase variants. The kinase assay linked with phosphoproteomics was applied as a high throughput technique to increase the known FLT3 kinase substrates (WT, ITD and D835Y) that were used to identify the FLT3 kinase variant’s preferred kinase sequence using the KINATEST-ID substrate predictive pipeline. The identified substrate sequence was used to synthesize and validate pan-FLT3 artificial substrates to monitor in vitro kinase activity in the presence of clinically relevant FLT3 TKI.

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2013-01-30 | E-GEOD-42109 | biostudies-arrayexpress

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2018-02-16 | GSE104594 | GEO

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