Abstract
Resistance to radiation therapy is a significant problem in the treatment of non-small cell lung cancer (NSCLC). There is an unmet need to discover new molecular targets for drug development in combination with standard of care cancer therapy. We found that TAF15 was radiation-inducible using phage-displayed peptide libraries. In this study, we report that overexpression of TAF15 is correlated with worsened survival in NSCLC patients. Radiation treatment led to surface induction of TAF15 in vitro and in vivo. We genetically silenced TAF15 which led to a significant reduction in proliferation of NSCLC cells. Cells depleted of TAF15 exhibited cell cycle arrest and enhanced apoptosis through activation and accumulation of p53. In combination with radiation, TAF15 knockdown led to a significant reduction in the surviving fraction of NSCLC cell lines. To determine the importance of TAF15 surface expression, we targeted TAF15 with an antibody. In combination with radiation, the anti-TAF15 antibody led to a reduction in the surviving fraction of cancer cells. These studies show that TAF15 is a radiation-inducible molecular target that is accessible to anti-cancer antibodies and enhances cell viability in response to radiation.
Highlights
Resistance to therapy is a significant challenge during the treatment of non-small cell lung cancer (NSCLC)
To determine if the expression of TATA-box-binding protein-associated factor 15 (TAF15) associated with overall survival (OS) in NSCLC patients, we analyzed the RNA-Seq data for cancer (Cancer Genome Atlas (TCGA)) (3) and healthy tissue (Genotype-Tissue Expression (GTEx)) (4,5) using the web-based Gene Expression Profiling Interactive Analysis (GEPIA)
Higher expression levels of TAF15 significantly correlated (p = 0.035, HR = 1.4) with a worsened OS of lung adenocarcinoma patients (Figure 1A). This difference in survival was not observed until 2000 days, and in the case of squamous cell carcinoma patients, we did not find a correlation between TAF15 expression levels and overall survival (Supplementary Figure 1A)
Summary
Resistance to therapy is a significant challenge during the treatment of non-small cell lung cancer (NSCLC). NSCLC ranks among the most common type of malignancy and is the leading cause of cancer-related deaths worldwide [1, 2]. Advancements in diagnosis and treatment have improved the survival of patients with lung cancer, the 5-year overall survival rate of NSCLC is ~19% [3]. There is an unmet need to develop novel treatment strategies for lung cancer patients. The demand is even higher for patients who have locally advanced, unresectable cancer. Targeted therapy is a growing topic of investigation for improving the current treatment strategies. The purpose of the present study is to discover additional molecular targets that complement and enhance the efficacy of standard of care chemotherapy and radiation therapy (XRT)
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