A multimodal approach for establishing and as chemoresistance genes in locally advanced head and neck cancer.

BACKGROUND

DNA is generally considered the ultimate target of cisplatin, so DNA repair has become the hallmark for cisplatin chemoresistance that is attributed to the poor overall survival (50%) among patients with head and neck cancer (HNC). As the efficacy of cisplatin is dose-dependent, we conducted the first study in an Asian population to characterize the DNA repair genes and based on the dosing of cisplatin-based chemoradiotherapy (CRT).

METHODS

Locally advanced HNC (LAHNC) patients who were planning to undergo cisplatin-based CRT were enrolled in a prospective study to quantify the dose-dependent expressions of and from peripheral blood mononuclear cells via quantitative polymerase chain reaction; these results were integrated with computational analysis and systematic review/meta-analysis to formulate evidence-based translation decisions. The Friedman test and Wilcoxon's test were used to compare the expressions of the two genes before and after CRT, and Spearman's rank correlation was used to find the correlation between and expressions. All statistical analyses were performed using SPSS version 29.

RESULTS

A total of 77 LAHNC patients were enrolled in this study, of which 96.1% were men and 3.9% were women with a mean age of 52.88 ± 9.68 years. The median expressions of were significantly increased ( < 0.001) after 50% (0.19) and 100% CRT (0.23) compared to the baseline value (0.14), whereas expression decreased from 4.77 to 3.87 after 50% CRT ( < 0.05) and increased to 5.43 after 100% CRT. From the computational analysis, and were found to be overexpressed among HNC patients and observed to regulate 10 repair pathways. Overexpressions of and were predicted to infiltrate the tumors with CD4 cells, macrophages, dendritic cells, and B cells. The hazard ratios for overall survival were found to be 1.67 among the overexpressed and 1.82 among the overexpressed HNC patients via computational analysis and meta-analysis, respectively. Furthermore, FDA-approved drugs like gemcitabine and panobinostat were found to be the best candidates for downregulating and expressions based on binding affinities of -3.707 and -4.198 kcal/mol, respectively.

CONCLUSION

The increased expressions of and during/after cisplatin-based CRT are expected to mediate DNA repair leading to chemoresistance, which could result in poor overall survival in HNC patients. Thus, FDA-approved drugs like panobinostat and gemcitabine can be repurposed to target the chemoresistance genes and , respectively.