Influence of MRE11, RAD50 and NIBRIN protein expression on survival in pancreatic carcinoma after curative resection

Horst, Klemens; Ganzera, Silke; Kaisers, Wolfgang; Münding, Johanna; Flott-Rahmel, B.; Tannapfel, Andrea; Zirngibl, Hubert

doi:10.1016/j.prp.2013.07.003

Cited by 3 publications

(2 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…44 Similar findings have been found for the other members of the MRN complex, with increased expression of MRE11 and NBS1 associated with shorter survival in CRC, 45 high expression of MRE11 combined with ATM associated with lower OS and disease-free survival in rectal cancer, 35 and high levels of NBS1 correlating with lower recurrence-free survival in EOC. 46 Not all studies agree, however, with some showing no prognostic value of MRE11 in anal cancers treated with chemo-radiotherapy, 47 and favourable prognosis of high NBS1 in pancreatic cancer, 48 highlighting differences in prognostic biomarkers between cancer types and different therapy regimens. It would be interesting to investigate further whether pRAD50 could be used as a prognostic marker as well as a PD biomarker and we note the additional possibility of interrogating pRAD50 on circulating tumour cells (CTCs) 49 as a potential clinically amenable surrogate tumour tissue assessment method.…”

Section: Discussionmentioning

confidence: 99%

pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry

et al. 2018

View full text Add to dashboard Cite

Background AZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangiectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage. Methods We used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue. Results We found moderate pRAD50 baseline levels across cancer indications. pRAD50 was detectable in 100% gastric cancers ( n = 23), 99% colorectal cancers ( n = 102), 95% triple-negative-breast cancers (TNBC) ( n = 40) and 87.5% glioblastoma-multiformes ( n = 16). We demonstrated AZD0156 target inhibition in TNBC patient-derived xenograft models; where AZD0156 monotherapy or post olaparib treatment, resulted in a 34–72% reduction in pRAD50. Similar inhibition of pRAD50 (68%) was observed following ATM inhibitor treatment post irinotecan in a colorectal cancer xenograft model. ATR inhibition, using AZD6738, increased pRAD50 in the ATM-proficient models whilst in ATM-deficient models the opposite was observed, suggesting pRAD50 pharmacodynamics post ATR inhibition may be ATM-dependent and could be useful to determine ATM functionality in patients treated with ATR inhibitors. Conclusion Together these data support clinical utilisation of pRAD50 as a biomarker of AZD0156 and AZD6738 pharmacology to elucidate clinical pharmacokinetic/pharmacodynamic relationships, thereby informing recommended Phase 2 dose/schedule.

show abstract

Section: Discussionmentioning

confidence: 99%

pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry

et al. 2018

View full text Add to dashboard Cite

show abstract

“…This partially explains the increased sensitivity to irradiation in the RAD50 knockdown cellsMutations in the genes encoding MRN complex have been shown to associate with risk for breast cancer [21]. Expression levels of MRE11, RAD50 and NIBRIN protein are found to be significantly correlated with the postoperative survival in patients with pancreatic ductal adenocarcinoma [22]. Recently, RAD50 has been found to be dysregulated in premalignant immortalized human colonic epithelial cells and may be implicated in early stage of CRC development [23,24].…”

Section: Effects Of Rad50 Knockdown On γ-H2ax Foci Formation After Irmentioning

confidence: 99%

Targeting RAD50 increases sensitivity to radiotherapy in colorectal cancer cells

Chen¹,

Wang²,

Mei³

et al. 2018

neo

View full text Add to dashboard Cite

Radiotherapy resistance remains the major factor limiting the radiotherapy efficacy in colorectal cancer. The Mre11-RAD50-Nbs1 (MRN) complex is known to play a critical role in the DNA double strand breaks (DSBs) repair pathways and thus facilitates radioresistance. Targeting MRN function can sensitize cancer cells to irradiation in some malignancies. In this study, we stably knocked down RAD50 protein in colorectal cancer (CRC) cell lines, HCT116 and DLD1, and evaluated their response to irradiation as well as the DSB repair dynamics. We observed that downregulation of RAD50 sensitized CRC cells to irradiation with reduction in DSB repair efficiency after exposure to irradiation. In addition, RAD50 was found to be upregulated in CRC cancerous tissue samples compared to non-cancerous adjacent tissues (NATs) and in patients who were resistant to RT. Elevated RAD50 expression was associated with poor patient survival in CRC. In conclusion, targeting RAD50 can serve as an efficient strategy to sensitize CRC cells to irradiation. RAD50 protein may be used as a biomarker for patient survival in CRC.

show abstract

DNA damage response and repair in osteosarcoma: Defects, regulation and therapeutic implications

et al. 2021

View full text Add to dashboard Cite

Influence of MRE11, RAD50 and NIBRIN protein expression on survival in pancreatic carcinoma after curative resection

Cited by 3 publications

References 19 publications

pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry

pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry

Targeting RAD50 increases sensitivity to radiotherapy in colorectal cancer cells

DNA damage response and repair in osteosarcoma: Defects, regulation and therapeutic implications

Contact Info

Product

Resources

About