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Different regions of oral squamous cell carcinoma (OSCC) have particular histopathological and molecular characteristics limiting the standard tumor−node−metastasis prognosis classification. Therefore, defining biological signatures that allow assessing the prognostic outcomes for OSCC patients would be of great clinical significance. Using histopathology-guided discovery proteomics, we analyze neoplastic islands and stroma from the invasive tumor front (ITF) and inner tumor to identify differentially expressed proteins. Potential signature proteins are prioritized and further investigated by immunohistochemistry (IHC) and targeted proteomics. IHC indicates low expression of cystatin-B in neoplastic islands from the ITF as an independent marker for local recurrence. Targeted proteomics analysis of the prioritized proteins in saliva, combined with machine-learning methods, highlights a peptide-based signature as the most powerful predictor to distinguish patients with and without lymph node metastasis. In summary, we identify a robust signature, which may enhance prognostic decisions in OSCC and better guide treatment to reduce tumor recurrence or lymph node metastasis.

Oral cavity cancer (OCC) is associated with high incidence of loco-regional recurrences, which account for the majority of treatment failures post-surgery and radiotherapy. The time-course of relapse manifestation and metastasis are unpredictable. Relapsed OCC represents a major clinical challenge in part due to their aggressive and invasive behaviors. Chemotherapy remains the only option for advanced OCC whenever salvage surgery or re-irradiation is not feasible, but its efficacy is limited as a result of the drug resistance development. Alternatives to use of different permutations of standard cytotoxic drugs or combinations with modulators of drug resistance have led to incremental therapeutic benefits. The introduction of targeted agents and biologics against selective targets that drive cancer progression has opened-up optimism to achieve superior therapeutic activity and overcome drug resistance because, unlike the non-selective cytotoxic, the target can be monitored at molecular levels to identify patients who can benefit from the drug. This review discusses the multifactorial aspects of clinical drug resistance and emerging therapeutic approaches in recurrent OCC, emphasizing recent advances in targeted therapies, immunotherapy, and potential relevance of new concepts such as epithelial-mesenchymal transition and cancer stem cell hypothesis to drug resistance.

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