Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy

Willoughby, Catherine E.; Jiang, Yanyan; Thomas, Huw D.; Willmore, Elaine; Kyle, Suzanne; Wittner, Anita; Phillips, Nicole; Zhao, Yan; Tudhope, Susan J.; Prendergast, Lisa; Junge, G.C.A.; Lourenco, Luiza Madia; Finlay, M. Raymond V.; Turner, Peter G.; Munck, Joanne M.; Griffin, Roger J.; Rennison, Tommy; Pickles, James; Cano, Céline; Newell, David R.; Reeves, Helen L.; Ryan, Anderson J.; Wedge, Stephen R.

doi:10.1172/jci127483

Cited by 49 publications

(45 citation statements)

References 53 publications

(55 reference statements)

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“…Additionally, DNA-PK has an RNA-dependent, cNHEJ-independent function during ribosome biogenesis that requires kinase activity of DNA-PKcs [ 37 ]. Based on these features, DNA-PKcs often protects tumor cells from DNA damage that derives from chemotherapy and radiotherapy [ 38 – 41 ]. Specifically, DNA-PKcs promotes proliferation, inhibits apoptosis and facilitates DNA-repair of HCC cells independent of p53 [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated bioinformatic analysis of RNA binding proteins in hepatocellular carcinoma

Zhang

Wan

et al. 2020

Aging

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RNA binding proteins (RBPs) are aberrantly expressed in a tissue-specific manner across many tumors. These proteins, which play a vital role in post-transcriptional gene regulation, are involved in RNA splicing, maturation, transport, stability, degradation, and translation. We set out to establish an accurate risk score model based on RBPs to estimate prognosis in hepatocellular carcinoma (HCC). RNA-sequencing data, proteomic data and corresponding clinical information were acquired from the Cancer Genome Atlas database and the Clinical Proteomic Tumor Analysis Consortium database respectively. We identified 406 differentially expressed RBPs between HCC tumor and normal tissues at the transcriptional and protein level. Overall, 11 RBPs (BRIX1, DYNC1H1, GTPBP4, PRKDC, RAN, RBM19, SF3B4, SMG5, SPATS2, TAF9, and THOC5) were selected to establish a risk score model. We divided HCC patients into low-risk and high-risk groups based on the median of risk score values. The survival analysis indicated that patients in the high-risk group had poorer overall survival compared to patients in the low-risk group. Our study demonstrated that 11 RBPs were associated with the overall survival of HCC patients. These RBPs may represent potential drug targets and can help optimize future clinical treatment.

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Section: Discussionmentioning

confidence: 99%

Integrated bioinformatic analysis of RNA binding proteins in hepatocellular carcinoma

Zhang

Wan

et al. 2020

Aging

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“…Overexpression of DNA-PKcs is frequent in a variety of cancer types and predicts poor prognosis in patients [ 9 , 10 , 11 , 12 , 13 , 14 ]. Consequently, DNA-PKcs has been shown to be a potential therapeutic target, especially in combination with radio- and chemotherapy that induce DNA damage [ 2 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity

Yang

Yao

Marti

et al. 2020

Cancers

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The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key component of the DNA-PK complex that has a well-characterized function in the non-homologous end-joining repair of DNA double-strand breaks. Since its identification, a large body of evidence has demonstrated that DNA-PKcs is frequently overexpressed in cancer, plays a critical role in tumor development and progression, and is associated with poor prognosis of cancer patients. Intriguingly, recent studies have suggested novel functions beyond the canonical role of DNA-PKcs, which has transformed the paradigm of DNA-PKcs in tumorigenesis and has reinvigorated the interest to target DNA-PKcs for cancer treatment. In this review, we update recent advances in DNA-PKcs, in particular the emerging roles in tumor metastasis, metabolic dysregulation, and immune escape. We further discuss the possible molecular basis that underpins the pleiotropism of DNA-PKcs in cancer. Finally, we outline the biomarkers that may predict the therapeutic response to DNA-PKcs inhibitor therapy. Understanding the functional repertoire of DNA-PKcs will provide mechanistic insights of DNA-PKcs in malignancy and, more importantly, may revolutionize the design and utility of DNA-PKcs-based precision cancer therapy.

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“…Presently, it is not clear whether transient pharmacological inhibition of DNA-PKcs can be applied jointly with radiation without increasing toxicity at the same time. Willoughby et al [ 103 ] reported the identification of NU5455, a novel highly selective orally bioavailable inhibitor of DNA-PKcs activity. NU5455 was used to evaluate pharmacological DNA-PKcs inhibition in combination with RT in a cell line panel, including HCC cell lines, by examining the responses of both tumor and normal tissues to treatment.…”

Section: Radiosensitization Strategiesmentioning

confidence: 99%

Stereotactic Radiotherapy for Hepatocellular Carcinoma, Radiosensitization Strategies and Radiation-Immunotherapy Combination

Pérez-Romasanta

Portillo

Rodríguez-Gutierrez

et al. 2021

Cancers

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Stereotactic body radiotherapy (SBRT) is an emerging ablative modality for hepatocellular carcinoma (HCC). Most patients with HCC have advanced disease at the time of diagnosis, and therefore, are not candidates for definitive-intent therapies such as resection or transplantation. For this reason, various alternative local and regional therapies have been used to prevent disease progression, palliate symptoms, and delay liver failure. Stereotactic body radiation therapy is a non-invasive technique of delivering ablative doses of radiation to tumors while sparing normal or non-tumor hepatic tissue. Incorporation of SBRT in multidisciplinary HCC management is gradual, initially applied when other liver-directed therapies have failed or are contraindicated, and tried in combination with other locoregional or systemic therapies for more unfavorable conditions by more experienced teams. In order to improve SBRT therapeutic ratio, there has been much interest in augmenting the effect of radiation on tumors by combining it with chemotherapy, molecularly targeted therapeutics, nanoparticles, and immunotherapy. This review aims to synthesize available evidence to evaluate the clinical feasibility and efficacy of SBRT for HCC, and to explore novel radio-potentiation concepts by combining SBRT with novel therapeutics. It is expected that those approaches would result in improved therapeutic outcomes, even though many questions remain with regard to the optimal way to assemble treatments. Further trials are needed to evaluate and consolidate these promising therapies for HCC.

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Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy

Cited by 49 publications

References 53 publications

Integrated bioinformatic analysis of RNA binding proteins in hepatocellular carcinoma

Integrated bioinformatic analysis of RNA binding proteins in hepatocellular carcinoma

Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity

Stereotactic Radiotherapy for Hepatocellular Carcinoma, Radiosensitization Strategies and Radiation-Immunotherapy Combination

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