TRIP13 and germline gene expression in cancer Mechanisms of acquired radioresistance

Cancer is a major global health challenge, characterized by increasing incidence rates and significant therapeutic obstacles. Despite the diversity among cancer types, they share common characteristics, referred to as the hallmarks of cancer, which serve as critical drivers of tumor progression. These hallmarks have been effectively exploited as therapeutic targets, given their essential role in supporting cancer cell proliferation and survival. Recent research has identified a subset of germline-cancer (GC) genes—normally restricted to germline cells but aberrantly expressed in tumors—that regulate key processes such as meiosis, gene regulation, and DNA repair, with their activation linked to poor prognosis. In this thesis, we demonstrate that high GC gene expression in lung cancer cell lines is associated with enhanced DNA double-strand break (DSB) repair, increased proliferation, and radioresistance. Among these genes, TRIP13 was identified as a key driver of this phenotype. Functional studies showed that TRIP13 inhibition or knockout reduces clonogenic survival, sensitizes cells to ionizing radiation, and downregulates DNA repair proteins. Repeated radiation exposure induced TRIP13 expression, conferring acquired radioresistance and correlating with poor prognosis in lung cancer patients.

Moreover, we show that melatonin (MT), acting via the MTNR1B receptor, downregulates TRIP13 and its downstream DNA repair proteins. TRIP13 inhibition also diminished EGFR expression and phosphorylation, indicating additional oncogenic functions beyond DNA repair. Collectively, these findings uncover a novel mechanism of therapeutic resistance driven by aberrant germline gene activation and highlight TRIP13 as a promising therapeutic target to enhance the efficacy and specificity of lung cancer treatment.