A Combined Systemic Strategy for Overcoming Cisplatin Resistance in Head and Neck Cancer: From Target Identification to Drug Discovery

SIMPLE SUMMARY: The efficiency of cisplatin is limited by drug resistance in head–neck cancer (HNC) patients. In this study, we established a cisplatin resistance (CR) cell model, generated CR related transcriptome profiling, and combined application of bioinformatics methodology to discover a possible way to overcome CR. Analysis of the functional pathway revealed that mitotic division is a novel mechanism significantly contributing to CR. Spindle pole body component 25 (SPC25), a kinetochore protein, was overexpressed in CR cells and significantly correlated with worse HNC patient survival. The silencing of SPC25 increased cisplatin sensitivity and reduced cancer stemness property. Integration of CR transcriptome profiling and drug database discovered a natural extract compound, celastrol, possessing a potent cytotoxic effect in CR cells to reverse CR. Thus, we combined systemic strategies to demonstrated that a novel biological process (mitotic cell division), a hub gene (SPC25), and a natural compound (celastrol) as novel strategies for the treatment of refractory HNC. ABSTRACT: Cisplatin is the first-line chemotherapy agent for head and neck cancer (HNC), but its therapeutic effects are hampered by its resistance. In this study, we employed systemic strategies to overcome cisplatin resistance (CR) in HNC. CR cells derived from isogenic HNC cell lines were generated. The CR related hub genes, functional mechanisms, and the sensitizing candidates were globally investigated by transcriptomic and bioinformatic analyses. Clinically, the prognostic significance was assessed by the Kaplan–Meier method. Cellular and molecular techniques, including cell viability assay, tumorsphere formation assay, RT-qPCR, and immunoblot, were used. Results showed that these CR cells possessed highly invasive and stem-like properties. A total of 647 molecules was identified, and the mitotic division exhibited a novel functional mechanism significantly related to CR. A panel of signature molecules, MSRB3, RHEB, ULBP1, and spindle pole body component 25 (SPC25), was found to correlate with poor prognosis in HNC patients. SPC25 was further shown as a prominent molecule, which markedly suppressed cancer stemness and attenuated CR after silencing. Celastrol, a nature extract compound, was demonstrated to effectively inhibit SPC25 expression and reverse CR phenotype. In conclusion, the development of SPC25 inhibitors, such as the application of celastrol, maybe a novel strategy to sensitize cisplatin for the treatment of refractory HNC.