2812 - Inhibition of Tumor-Intrinsic BANF1 Sheds Light on Lung Cancer Radiotherapy

Y. Huang¹, M. Wang¹, M. Wu¹, D. Chen¹, and J. Yu²; ¹Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, ²Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

Inhibition of tumor intrinsic BANF1 sheds light on treating lung cancer Purpose/Objective(s): It is universally recognized that lung cancer is the leading form of cancer globally, and radiotherapy remains its most effective treatment. Nevertheless, resistance to radiotherapy is a common occurrence in lung cancer. Therefore, to delve deeper into the mechanisms underlying this resistance and optimize the benefits of radiotherapy for lung cancer patients, it is imperative for us to seek potential biological targets at the molecular level. In our prior research, we have discovered that BANF1 plays a pivotal role in DNA damage repair response and mediates the resistance to radiotherapy in lung cancer. Materials/

Methods: In our prior research, we successfully knocked down BANF1 in lung cancer cell lines and subsequently analyzed the apoptosis of these cells post-radiotherapy using flow cytometry. Moreover, we utilized transwell assays to assess the invasion and migration capabilities of the cells following radiotherapy. Additionally, comet assays were conducted to detect the extent of DNA damage in the cells after radiotherapy. To further our understanding, we implanted lung cancer cell lines with BANF1 knockdown into immunodeficient mice and closely monitored the status and tumor growth of both the experimental and control groups post-radiotherapy.
Results: Cells exhibiting radioresistance after ionizing radiation show upregulation of BANF1, while the knockdown of BANF1 can increase the radiosensitivity of tumors in vitro and in vivo. Functionally, BANF1 deficiency can reduce homologous recombination repair, increase apoptosis, and inhibit migration and invasion ability. Mechanistically, knocking down BANF1 can inhibit the accumulation of p-ATM and its downstream repair protein RAD51 during DNA repair. In addition, BANF1 can directly interact with the MRN complex upstream of A homologous recombination to promote the phosphorylation level of ATM during homologous recombination-mediated DNA double-strand break repair. Meanwhile, high expression of BANF1 is also associated with poor prognosis in patients with lung cancer at the clinical level.
Conclusion: Inhibiting tumor-intrinsic BANF1 holds the potential to significantly enhance the radiosensitivity of lung cancer patients, thus bringing renewed hope for their successful treatment. As a dynamic dsDNA sensor, BANF1 exhibits the ability to bind to both nuclear genomic DNA and cytosolic dsDNA. Recent investigations have revealed that the absence of BANF1 in mouse microglial cells results in a surge in cytosolic dsDNA levels and a subsequent augmentation of the innate immune response. In essence, our discoveries unveil a previously unknown regulatory mechanism through which BANF1 governs the radiosensitivity of lung cancer. Looking ahead, our future endeavors will be focused on exploring clinical inhibitors of BANF1, with the aim of further advancing lung cancer treatment options.