Targeting polymerase θ impairs tumorigenesis and enhances radiosensitivity in lung adenocarcinoma

Radioresistance remains a major obstacle to efficacious radiotherapy in non-small-cell lung cancer (NSCLC). DNA replication proteins are novel targets for radiosensitizers. POLQ is a DNA polymerase involved in DNA damage response and repair. We found that POLQ is overexpressed in NSCLC and is clinically correlated with high tumor stage, poor prognosis, increased tumor mutational burden, and ALK and TP5 mutation status; POLQ inhibition impaired lung tumorigenesis. Notably, POLQ expression was higher in radioresistant lung cancer cells than in wild-type cancer cells. Moreover, POLQ expression was further increased in radioresistant cells after radiation. Enhanced radioresistance is through a prolonged G2/M phase and faster repair of DNA damage, leading to reduced radiation-induced apoptosis. Novobiocin (NVB), a POLQ inhibitor, specifically targeted cancer cells. Genetic knockdown of POLQ or pharmacological inhibition by NVB decreased radioresistance in lung adenocarcinoma while causing little toxicity to normal pulmonary epithelial cells. In conclusion, POLQ is a promising and practical cancer-specific target to impair tumorigenesis and enhance radiosensitivity in NSCLC.

Automated summary

POLQ, an overexpressed DNA polymerase in non-small-cell lung cancer (NSCLC), is correlated with high tumor stage, poor prognosis, increased tumor mutational burden, and ALK and TP5 mutation status. Inhibition of POLQ impairs lung tumorigenesis and enhances radiosensitivity by prolonging the G2/M phase and promoting faster DNA damage repair. Novobiocin (NVB), a specific POLQ inhibitor, targets cancer cells without causing significant toxicity to normal pulmonary epithelial cells. These findings suggest that POLQ is a promising target for improving radiotherapy efficacy in NSCLC.