Introduction: Osteosarcoma is the most common bone tumor in children and adolescents. Many patients have disease progression through standard chemotherapy regimens of methotrexate, cisplatin, and doxorubicin. Presently, there are no salvage therapies that have added significant survival benefits, leaving minimal options for relapsed and resistant disease. Additionally, there are no clinically significant biomarkers for this disease that would predict treatment failures. N-acetylgalactosaminyltransferase 14 (GALNT14) is an enzyme that initiates O-linked glycosylation to outer membrane-bound and extracellular proteins. Using transcriptomic analyses, we identified GALNT14 overexpression correlated with poor tumor necrosis and survival outcomes. Therefore, we hypothesize that GALNT14 contributes to metastatic and chemoresistant phenotypes in pediatric osteosarcoma.

Methods: Transcriptomic data from the Therapeutically Applicable Research for Generating Effective Treatments (TARGET) database and RNA-sequencing of institutional patient-derived xenografts (PDXs) revealed that overexpression of GALNT14 correlated to poor necrosis rates. Gene Set Enrichment Analysis (GSEA) also identified upregulation of glycosylation pathways. Aberrant expression of GALNT14 was confirmed using quantitative polymerase chain reaction (qPCR) and Western blot analyses in various osteosarcoma cell lines. Transient GALNT14 knockdown and overexpression were then analyzed for effects on proliferation, invasion, migration, and chemotherapy response in vitro. Kaplan-Meier curves demonstrating overall survival (OS) and event-free survival (EFS) were established using data from the TARGET database.

Results: GALNT14 expression was higher in both commercial and PDX cell lines that were known to be more prone for chemoresistance and invasiveness. The highest quartile of patients based on GALNT14 overexpression had 40% OS and 25% EFS, compared to 80% (p=0.002) and 75% (p<0.001) for the lowest quartile of expression, respectively.

Summary: GALNT14 shows promise as a predictive marker of chemoresistance and metastasis for pediatric osteosarcoma. Future functional genomic studies through gain and loss-of-function assays will evaluate the role of GALNT14 in osteosarcoma chemoresistance and metastatic potential.

Citation Format: Zachary D. Prudowsky, Tajhal Patel, Kimal Rajapakshe, Christian Coarfa, Ryan Shuck, Nino Rainusso, Jason Yustein. The role of GALNT14 in chemoresistant and metastatic osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 405.