Targeting polymerase θ impairs tumorigenesis and enhances radiosensitivity in lung adenocarcinoma.
Xinrui RaoBiyuan XingZilong WuYawen BinYunshang ChenYingzhuo XuDong ZhouXiaoshu ZhouChuangyan WuWang YeWeibin ChenGeng WangSheng ZhangXiaorong DongRui MengGang WuRui ZhouPublished in: Cancer science (2023)
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.
Keyphrases
- poor prognosis
- induced apoptosis
- dna damage response
- oxidative stress
- long non coding rna
- small cell lung cancer
- dna damage
- advanced non small cell lung cancer
- endoplasmic reticulum stress
- signaling pathway
- dna repair
- wild type
- early stage
- radiation therapy
- cancer therapy
- radiation induced
- binding protein
- pulmonary hypertension
- squamous cell carcinoma
- drug delivery
- cancer stem cells
- genome wide
- epidermal growth factor receptor
- cell proliferation
- cell death
- copy number