MicroRNA expression patterns predict a chemotherapy resistance phenotype in osteosarcoma
Embargo Date
2026-02-28
OA Version
Citation
Abstract
Osteosarcoma is a rare primary bone tumor for which no significant therapeutic advancement has been made since the late 1980’s despite ongoing efforts. A subset of patients who share good prognosis respond well to the current chemotherapeutic regimen of methotrexate, doxorubicin, and cisplatin. However, pathologically assessed chemotherapy response has thus far failed as a tool to stratify patients to alternate therapies and improve patient outcomes. Aside from chemotherapy response, no other validated prognostic factor exists, and genetic studies have not revealed any actionable drug targets. We and others have previously reported that epigenomic biomarkers may be useful in this disease. We thus investigated the capacity for microRNAs to mark the transition from a chemotherapy sensitive to resistant tumor phenotype. We performed small RNA sequencing on a cohort of paired pre-chemotherapy and post-chemotherapy frozen high-grade osteosarcoma tumor samples and discovered a profile of miRNAs with dynamic expression patterns following chemotherapy exposure in patient samples. An independent dataset of paired pre-chemotherapy and post-chemotherapy formalin fixed paraffin embedded samples we assayed with array-based technology was used to show the miRNA profiles are reproducible. Transcriptional studies of the miRNAs’ target genes contextualize the potential biological role of the miRNAs. In a pharmacogenomic screen, both miRNAs and their target genes predict response to drugs which reverse the chemoresistant phenotype and potentially synergize with chemotherapy in otherwise treatment resistant tumors.
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License
Attribution-NonCommercial-NoDerivatives 4.0 International