A Multimodal Approach to Establish ACTL6A and ERCC1 as Chemoresistance Genes in Locally Advanced Head and Neck Cancer

Raushan Kumar Chaudhary¹PRAKASH PATIL²Vijith Shetty³UDAY VENKAT MATETI^1*Praveenkumar Shetty⁴

• ¹Nitte Gulabi Shetty Memorial Institute of Pharmaceutical Sciences, Mangalore, India
• ²Central Research Laboratory, K S Hegde Medical Academy, Mangalore, Karnataka, India
• ³K S Hegde Medical Academy, Mangalore, Karnataka, India
• ⁴Department of Biochemistry, K S Hegde Medical Academy, Mangalore, Karnataka, India

Background: DNA being an ultimate target of cisplatin, DNA repair becomes a hallmark to cisplatin chemoresistance which might be attributed to poor overall survival (50%) among Head and neck cancer (HNC) patients. As the efficacy of cisplatin is dose dependent, we conducted first Asian study to characterize DNA repair genes ACTL6A and ERCC1 across dosing of cisplatin-based chemoradiation therapy (CRT). Methods: Locally advanced HNC (LAHNC) patients planned to undergo cisplatin-based CRT were enrolled prospectively to quantify the dose dependent expression of ACTL6A and ERCC1 from Peripheral blood mononuclear cells (PBMCs) via qPCR which was integrated with computational analysis and systematic review/meta-analysis to make an evidence-based translation decision. Friedman test and Wilcoxon’s test was used to compared the expression of genes across/before-after CRT and Spearman’s rank test was used to find the correlation between ACTL6A and ERCC1 expression. All the Statistical analysis were performed using SPSS version 29.Results: A total of 77 LAHNC patients were enrolled of which 96.1% were male and 3.9% were female with the mean age 52.88±9.68 years. The median expression of ERCC1 was significantly (p-value<0.001) increased after 50% (0.19) and 100% CRT (0.23) in compared to baseline (0.14) whereas ACTL6A expression decreased from 4.77 to 3.87 after 50% CRT (p-value<0.05) and increased to 5.43 after 100% CRT. On computational analysis, ACTL6A and ERCC1 was found to be overexpressed among HNC patients and regulated 10 repair pathways. Overexpression of ERCC1 and ACTL6A predicted to infiltrate the tumor with CD4+, macrophage, dendritic, B cells. Further, the hazards on overall survival were found to be 1.67 among ACTL6A overexpressed and 1.82 among ERCC1 overexpressed HNC patients via computational analysis and meta-analysis respectively. Further, FDA approved drugs like Gemcitabine and Panobinostat was found to be best candidate to downregulate ERCC1 and ACTL6A expression with the binding affinity of -3.707 and -4.198 kcal/mol respectively. Conclusion: The increased expression of ACTL6A and ERCC1 during/after cisplatin-based CRT can mediate DNA repair leading to chemoresistance which might result into poor overall survival in HNC. Thus, FDA approved drugs like Panobinostat and Gemcitabine can be repurposed to target chemoresistance genes ACTL6A and ERCC1.