Cisplatin is a cornerstone chemotherapeutic agent commonly used in the treatment of osteosarcoma; however, the emergence of resistance remains a major obstacle, leading to therapy failure and poor prognosis [1]. Understanding the molecular mechanisms driving cisplatin resistance is crucial for developing effective therapeutic strategies [2,3]. In this study, we performed a comprehensive proteomic analysis of patient-derived osteosarcoma cells to identify key proteins and pathways involved in such resistance. Osteosarcoma cell lines, including five commercial and eight patient-derived xenograft (PDXCL) lines, were continuous exposed to gradually increasing cisPt concentrations to induce drug resistance. Cell viability was assessed after 72 hours of treatment to calculate the resistance index (RI = IC50resistant/IC50parental). It was found that after 1-8 months of cisplatin exposure, ~54% of the cell lines (5/5 commercial and 2/8 PDXCL) developed stable drug resistance, with similar RI values for cisplatin (3.67±1.22).

Using mass spectrometry-based protein profiling, we compared the proteomes of cisplatin-sensitive and cisplatin-resistant osteosarcoma cells, revealing significant alterations in proteins associated with DNA repair, oxidative stress response, and drug efflux mechanisms. As a result, the proteomic analysis revealed 8,033 common proteins to both sensitive and cisplatin-resistant models and identified a common treatment response signature of 192 proteins. PCA analysis revealed the existence of 3 main groups of cells biologically interrelated based on their proteomes.

The insights gained from this study offer potential avenues for overcoming cisplatin resistance in osteosarcoma. Identified proteins and pathways may serve as biomarkers for predicting treatment response or as targets for novel therapeutic interventions aimed at sensitising resistant cells to cisplatin.

References

[1] A. Abarrategi, J. Tornín, L. Martinez-Cruzado, et al. Stem Cells Int. 2016; 3631764.

[2] Fanelli M, Tavanti E, Patrizio MP, et al. Front Oncol. 2020; 10:331.

[3] He H, Ni J, Huang J. Oncol Lett. 2014; 7(5):1352-1362.