The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy

DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibi...

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Vydáno v:	Cancer biology & therapy Ročník 13; číslo 11; s. 1072 - 1081
Hlavní autoři:	Prevo, Remko, Fokas, Emmanouil, Reaper, Philip M., Charlton, Peter A., Pollard, John R., McKenna, W. Gillies, Muschel, Ruth J., Brunner, Thomas B.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Taylor & Francis 01.09.2012 Landes Bioscience
Témata:	Antineoplastic Combined Chemotherapy Protocols - pharmacology Ataxia Telangiectasia Mutated Proteins ATR Binding Biology Bioscience Calcium Cancer Cell Cell Cycle Checkpoints - drug effects Cell Cycle Checkpoints - radiation effects Cell Cycle Proteins - antagonists & inhibitors Cell Hypoxia - physiology Cell Line, Tumor chemotherapy Combined Modality Therapy Cycle Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacology DNA Damage DNA Repair Gemcitabine Humans hypoxia inhibitor Landes Organogenesis Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - enzymology Pancreatic Neoplasms - pathology Pancreatic Neoplasms - radiotherapy Phosphorylation Protein Serine-Threonine Kinases - antagonists & inhibitors Proteins Pyrazines - administration & dosage Pyrazines - pharmacology Radiation-Sensitizing Agents - pharmacology radiosensitivity Research Paper Signal Transduction Sulfones - administration & dosage Sulfones - pharmacology
ISSN:	1538-4047, 1555-8576, 1555-8576
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Abstract	DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2 /M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients.
AbstractList	DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2/M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients. DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2/M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients.DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2/M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients. DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G2/M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients. DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2 /M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients.
Author	Reaper, Philip M. McKenna, W. Gillies Muschel, Ruth J. Fokas, Emmanouil Pollard, John R. Brunner, Thomas B. Prevo, Remko Charlton, Peter A.
AuthorAffiliation	Vertex Pharmaceuticals (Europe) Ltd.; Abingdon, UK Gray Institute for Radiation Oncology and Biology; Oxford University; Oxford, UK
AuthorAffiliation_xml	– name: Vertex Pharmaceuticals (Europe) Ltd.; Abingdon, UK – name: Gray Institute for Radiation Oncology and Biology; Oxford University; Oxford, UK
Author_xml	– sequence: 1 givenname: Remko surname: Prevo fullname: Prevo, Remko – sequence: 2 givenname: Emmanouil surname: Fokas fullname: Fokas, Emmanouil – sequence: 3 givenname: Philip M. surname: Reaper fullname: Reaper, Philip M. – sequence: 4 givenname: Peter A. surname: Charlton fullname: Charlton, Peter A. – sequence: 5 givenname: John R. surname: Pollard fullname: Pollard, John R. – sequence: 6 givenname: W. Gillies surname: McKenna fullname: McKenna, W. Gillies – sequence: 7 givenname: Ruth J. surname: Muschel fullname: Muschel, Ruth J. – sequence: 8 givenname: Thomas B. surname: Brunner fullname: Brunner, Thomas B. email: thomas.brunner@uniklinikfreiburg.de
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/22825331$$D View this record in MEDLINE/PubMed
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Snippet	DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically...
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SubjectTerms	Antineoplastic Combined Chemotherapy Protocols - pharmacology Ataxia Telangiectasia Mutated Proteins ATR Binding Biology Bioscience Calcium Cancer Cell Cell Cycle Checkpoints - drug effects Cell Cycle Checkpoints - radiation effects Cell Cycle Proteins - antagonists & inhibitors Cell Hypoxia - physiology Cell Line, Tumor chemotherapy Combined Modality Therapy Cycle Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacology DNA Damage DNA Repair Gemcitabine Humans hypoxia inhibitor Landes Organogenesis Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - enzymology Pancreatic Neoplasms - pathology Pancreatic Neoplasms - radiotherapy Phosphorylation Protein Serine-Threonine Kinases - antagonists & inhibitors Proteins Pyrazines - administration & dosage Pyrazines - pharmacology Radiation-Sensitizing Agents - pharmacology radiosensitivity Research Paper Signal Transduction Sulfones - administration & dosage Sulfones - pharmacology
Title	The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy
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