Exploring pPAK1 and gH2AX Signaling axis as Therapeutic target to combat Radiation resistance in Head and Neck Cancers

Abstract

HNSCCs are usually diagnosed at later stages and are treated with multimodal treatment ie surgical resection and chemoradiotherapy CRT However HNSCCs are highly aggressive cancers showing higher rates of distant metastasis and recurrence due to various reasons such as formation of primary tumors at multiple sites second primary tumors via field cancerization and resistance to chemotherapy and radiation therapy With literature evidence we are aware that the oncogenic kinase p21 activated kinase 1 PAK1 is altered in many cancers and plays a major role in conferring chemoresistance PAK1 confers tamoxifen resistance in breast carcinoma gemcitabine resistance in pancreatic cancer and cisplatin resistance in lung carcinoma and so on Phosphorylation at serine threonine and tyrosine residues the post translational modification of PAK1 is crucial for its activity Therefore we seek to unravel the role of PAK1 upon radiation exposure in HNSCC It is known that PAK1 is overexpressed in HNSCC cell lines and tissues compared to normal Hence we showed that PAK1 is activated in HNSCC upon exposure to ionizing radiation PAK1 being the central hub for the activation of many oncogenic signaling pathways and considering its role in cytoskeletal and ECM remodelling EMT cell cycle and apoptosis targeting activated PAK1 might help in improving the radiosensitivity We also confirmed that activated PAK1 is connected with poor survival in HNSCC patients after radiation treatment In addition PAK1 activity is increased in radioresistant SCC131 cells and presented with aggressive features whereas PAK1 KO cells showed a decreased oncogenic potential and increased sensitivity to radiation therapy. Interestingly we also found that the DNA damage marker gamma H2AX is also elevated in radioresistant SCC131 cells This molecule is a docking hub for many DNA damage repair proteins and promotes non homologous end joining NHEJ or homologous recombination HR It is evident that elevated PAK1 activity induces gamma H2AX via MORC2 thereby increasing the D