A prognostic model of platinum resistance in osteosarcoma: Key roles of BNIP3, MYC, and ACTA2

Platinum resistance poses a significant challenge in the treatment of osteosarcoma, leading to poor prognosis and limited therapeutic options. This study aims to develop a prognostic model by analyzing platinum-resistant genes (PRGs), focusing on their roles in lysosomal function and immune suppression.

We conducted a univariable Cox analysis to identify diagnostic-related genes (PRGs) from a training cohort of osteosarcoma patients. Consensus clustering was performed to classify patients into platinum-resistant (C1) and non-platinum-resistant (C2) subtypes. Differential expression and functional enrichment analyses characterized subtype-specific pathways. A multigene risk signature was constructed using LASSO Cox regression and validated in an independent cohort. Kaplan-Meier (KM) and time-dependent ROC analyses assessed prognostic performance. Knockdown experiments were performed for BNIP3 and MYC to evaluate their roles in platinum resistance.

We identified 105 genes related to both survival and platinum resistance, classifying patients into two subtypes with distinct overall survival rates. The C1 subtype exhibited poorer overall survival, lower immune cell infiltration, and dysregulated lysosomal and receptor-signaling pathways compared to C2. Functional analysis revealed that upregulated genes in the C1 subtype were involved in structural and signaling receptor activities, while downregulated genes were linked to immune processes. Our risk model, which included BNIP3, MYC and ACTA2, demonstrated high prognostic accuracy. Survival analysis confirmed ACTA2 as a protective factor and BNIP3 and MYC as risk factors. siRNA-mediated silencing experiments supported the roles of BNIP3 and MYC in promoting platinum resistance through lysosomal function and immune suppression.

This study introduces a novel risk model based on BNIP3, MYC, and ACTA2 for predicting platinum resistance in osteosarcoma. BNIP3 and MYC function as critical risk factors, while ACTA2 acts as a protective factor. These findings may guide the development of targeted therapies to overcome platinum resistance in osteosarcoma.