Human single-stranded DNA protein 1 (hSSB1): a prognostic factor and target for non-small cell lung cancer (NSCLC) treatment

Introduction: Despite advances in NSCLC therapeutics, including small molecule and antibody based targeted therapies, the majority of patients with advanced disease will ultimately relapse. Lung cancer is characterized by genomic instability leading to tissue invasion, metastasis and resistance to systemic treatments. hSSB1 has a key role in the detection and repair of DNA damage (double- strand breaks, replication fork arrest and oxidative stress). Recently we demonstrated that hSSB1 is phosphorylated by DNA-PK in response to replication stress to promote cellular survival. Here we establish that hSSB1 is a prognostic factor for NSCLC a potential novel target for therapy. Methods: We analyzed the prognostic significance of hSSB1 mRNA expression from public on line databases and from protein expression in an NSCLC tissue macro-array (TMA) through hSSB1 immunohistochemistry. hSSB1 mRNA levels were analyzed in matched normal, tumour adenocarcinoma and squamous cell tumour samples. We explored the impact of hSSB1 expression on NSCLC cell line proliferation by depleting hSSB1 with specific small interfering (si)RNA. We also measured the impact of hSSB1 inhibition on NSCLC cells proliferation with the use of a DNA-PK inhibitor and a novel agent, DKLS02. Results: hSSB1 expression was associated with poor prognosis for lung cancer, high levels of mRNA and protein expression correlating with a worse overall survival. We also observed that hSSB1 depletion leads to increased lung cancer cell death. The same result was observed when inhibiting hSSB1 by treating lung cancer cells with a DNA-PK inhibitor. Targeting hSSB1 with DKLS02 induces cell death in vitro and inhibits tumour growth in vivo in platinum sensitive and resistant tumours. Conclusion: Our results indicate that hSSB1 is a prognostic factor in NSCLC. Moreover, targeting hSSB1 may prove to be an effective therapeutic strategy for the treatment of chemosenstive and resistant NSCLC in the future. Disclosure: All authors have declared no conflicts of interest.