Pharmacologic inhibition of ataxia telangiectasia and Rad3‐related (ATR) in the treatment of head and neck squamous cell carcinoma

Karukonda, Pooja; Odhiambo, Diana; Mowery, Yvonne M.

doi:10.1002/mc.23384

Cited by 16 publications

(5 citation statements)

References 188 publications

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“…We used novel small molecule inhibitors targeting key proteins of DNA damage response pathways [ 37 ], such as DNA-PK, as an emerging therapeutic target in cancer [ 38 ]. Similar compounds of these novel classes of drugs targeting ATR and DNA-PK have already demonstrated a radiosensitizing effect in various types of cancer cells [ 9 , 13 , 14 , 39 , 40 , 41 ]. Previously, Dillon et al studied the ATR inhibitor AZD6738 (Ceralasertib) in DNA-PK deficient NOD SCID gamma mice, demonstrating an appropriate tolerance of this drug [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Effective Radiosensitization of Bladder Cancer Cells by Pharmacological Inhibition of DNA-PK and ATR

et al. 2022

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This study aims at analyzing the impact of the pharmacological inhibition of DNA damage response (DDR) targets (DNA-PK and ATR) on radiosensitization of bladder cancer cell lines of different molecular/histological subtypes. Applying DNA-PK (AZD7648) and ATR (Ceralasertib) inhibitors on SCaBER, J82 and VMCUB-1 bladder cancer cell lines, we revealed sensitization upon ionizing radiation (IR), i.e., the IC50 for each drug shifted to a lower drug concentration with increased IR doses. In line with this, drug exposure retarded DNA repair after IR-induced DNA damage visualized by a neutral comet assay. Western blot analyses confirmed specific inhibition of targeted DDR pathways in the analyzed bladder cancer cell lines, i.e., drugs blocked DNA-PK phosphorylation at Ser2056 and the ATR downstream mediator CHK1 at Ser317. Interestingly, clonogenic survival assays indicated a cell-line-dependent synergism of combined DDR inhibition upon IR. Calculating combined index (CI) values, with and without IR, according to the Chou–Talalay method, confirmed drug- and IR-dose-specific synergistic CI values. Thus, we provide functional evidence that DNA-PK and ATR inhibitors specifically target corresponding DDR pathways retarding the DNA repair process at nano-molar concentrations. This, in turn, leads to a strong radiosensitizing effect and impairs the survival of bladder cancer cells.

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Section: Discussionmentioning

confidence: 99%

Effective Radiosensitization of Bladder Cancer Cells by Pharmacological Inhibition of DNA-PK and ATR

et al. 2022

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“…Eight of them are currently under development [101], among which ceralasertib is included in DrugBank. These kinds of inhibitors were shown to be effective, especially in the treatment of head and neck squamous cell carcinoma, in combination with other therapies such as surgery, RT, and chemotherapy [176]. They also specifically target DDR pathways and impair DSB repair processes, exhibiting significant radiosensitizing effects [177].…”

Section: Targeting Essential Phosphorylation Factors For Regulating Ddrmentioning

confidence: 99%

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

Xie

Zhou

2023

IJMS

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DNA damage in astronauts induced by cosmic radiation poses a major barrier to human space exploration. Cellular responses and repair of the most lethal DNA double-strand breaks (DSBs) are crucial for genomic integrity and cell survival. Post-translational modifications (PTMs), including phosphorylation, ubiquitylation, and SUMOylation, are among the regulatory factors modulating a delicate balance and choice between predominant DSB repair pathways, such as non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we focused on the engagement of proteins in the DNA damage response (DDR) modulated by phosphorylation and ubiquitylation, including ATM, DNA-PKcs, CtIP, MDM2, and ubiquitin ligases. The involvement and function of acetylation, methylation, PARylation, and their essential proteins were also investigated, providing a repository of candidate targets for DDR regulators. However, there is a lack of radioprotectors in spite of their consideration in the discovery of radiosensitizers. We proposed new perspectives for the research and development of future agents against space radiation by the systematic integration and utilization of evolutionary strategies, including multi-omics analyses, rational computing methods, drug repositioning, and combinations of drugs and targets, which may facilitate the use of radioprotectors in practical applications in human space exploration to combat fatal radiation hazards.

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“…Chemoresistance of these tumors often limits the therapeutic effect of these treatments and causes unnecessary physical morbidity and economic burden to patients. Therefore, it is imperative to find targets and molecular biomarkers of chemoresistance for better treatment of HNSCC patients 7–10 …”

Section: Introductionmentioning

confidence: 99%

“…Therefore, it is imperative to find targets and molecular biomarkers of chemoresistance for better treatment of HNSCC patients. [7][8][9][10] At present, traditional Chinese medicine shows great potential in improving body immunity, reducing drug chemical toxicity, promoting tumor cell apoptosis, and enhancing the sensitivity of these tumors to chemotherapeutic drugs. HNSCC is commonly recognized as a qi and blood condensation type in Chinese medicine identification.…”

Section: Introductionmentioning

confidence: 99%

Expression of RIPK1 and FADD are associated with chemosensitivity and survival in head and heck squamous cell carcinoma via tanshinone IIA‐mediated modulation of the RIPK1‐FADD‐Caspase 8 complex

Shen,

Han,

Tan

et al. 2024

Molecular Carcinogenesis

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Tanshinone IIA (Tan IIA), a main active ingredient of salvia miltiorrhiza, has a wide range of antitumor effects, while its specific role and mechanism in head and neck squamous cell carcinomas (HNSCC) is not fully understood. Totally 59 primary HNSCC patients underwent two courses of induction chemotherapy before surgery. The association between expression of Fas‐Associated Death Domain (FADD) and receptor interacting protein kinase 1 (RIPK1) and chemotherapy resistance and survival were evaluated. The cell counting kit‐8 was used to detect the effect of Tan IIA on the activity of cisplatin in chemoresistant HNSCC cells through a series of in vitro experiments. The quantitative real‐time reverse‐transcription polymerase chain reaction, Western blot analysis and flow cytometry were used. FADD and RIPK1 expressions were differentially expressed in Chemosensitive and drug‐resistant patients. Furthermore, patients with tumors exhibiting high expression of FADD and RIPK1 had significantly greater risk for chemoresistance and mortality than patients with tumors that had low levels of these proteins. Moreover, Tan IIA reduced the expression of RIPK1 and FADD in HNSCC chemoresistant cell lines, which could increase the chemosensitivity of cisplatin and promote apoptosis. Overexpression of RIPK1 led to attenuation of therapeutic effects of Tan IIA, which were mainly realized through regulation of the RIPK1‐FADD‐Caspase 8 complex. This study is the first to demonstrate the clinical value and role of FADD and RIPK1 in the treatment of HNSCC. This work establishes the proapoptotic effects of Tan IIA and its potential to enhance chemosensitivity in HNSCC by modulating the RIPK1‐FADD‐Caspase 8 complex.

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Pharmacologic inhibition of ataxia telangiectasia and Rad3‐related (ATR) in the treatment of head and neck squamous cell carcinoma

Cited by 16 publications

References 188 publications

Effective Radiosensitization of Bladder Cancer Cells by Pharmacological Inhibition of DNA-PK and ATR

Effective Radiosensitization of Bladder Cancer Cells by Pharmacological Inhibition of DNA-PK and ATR

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

Expression of RIPK1 and FADD are associated with chemosensitivity and survival in head and heck squamous cell carcinoma via tanshinone IIA‐mediated modulation of the RIPK1‐FADD‐Caspase 8 complex

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