Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970

@article{Hall2014PotentiationOT,
  title={Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970},
  author={Amy B. Hall and D. Newsome and Yuxin Wang and D. Boucher and B. Eustace and Yong Gu and B. Hare and Mac A. Johnson and Sean Milton and Cheryl E. Murphy and Darin Takemoto and C. Tolman and M. Wood and P. Charlton and J. Charrier and Brinley F Furey and J. Golec and P. Reaper and J. Pollard},
  journal={Oncotarget},
  year={2014},
  volume={5},
  pages={5674 - 5685}
}
Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we… Expand

Paper Mentions

Interventional Clinical Trial
Background: Chemotherapy damages cancer cell DNA so the cells die and the tumor shrinks. But it may stop working in some people over time. This is partly due to efficient DNA… Expand
ConditionsCarcinoma, Neuroendocrine, Carcinoma, Non-Small -Cell Lung, Extrapulmonary Small Cell Cancer, (+3 more)
InterventionDrug
Targeting ATR for Cancer Therapy: Profile and Expectations for ATR Inhibitors
ATR is a highly versatile player in the DNA damage response (DDR) that signals DNA damage via CHK1 phosphorylation to the S and G2/M cell cycle checkpoints and to promote DNA repair. It is activatedExpand
Remarkable response to a novel ATR inhibitor in a patient with poorly differentiated neuroendocrine carcinoma.
TLDR
A case of a patient with metastatic prostate cancer with clonal evolution to poorly differentiated large cell neuroendocrine carcinoma who developed an exceptional response to treatment with M6620 and cisplatin on a phase I trial with over 20 months of non-CNS progression free survival is reported. Expand
Progress towards a clinically-successful ATR inhibitor for cancer therapy
TLDR
This review focuses on the biology of ATR, its functional role in cancer development and treatment, and the rationale behind inhibition of this target as a therapeutic approach, including evaluation of the progress and current status of development of potent and specific ATR inhibitors that have emerged in recent decades. Expand
Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations?
TLDR
The pre-clinical data supporting the use of ATR inhibitors as monotherapy and in combination with chemotherapy, radiotherapy and novel targeted agents such as PARP inhibitors are summarised. Expand
ATR/CHK1 inhibitors and cancer therapy.
  • Z. Qiu, N. Oleinick, Junran Zhang
  • Chemistry, Medicine
  • Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
  • 2018
TLDR
The status of the development of ATR/CHK1 inhibitors is reviewed and the potential mechanisms by which ATR and CHK1 inhibition induces cell killing in the presence or absence of exogenous DNA damaging agents, such as RT and chemotherapeutic agents are discussed. Expand
ATR kinase inhibition sensitizes quiescent human cells to the lethal effects of cisplatin but increases mutagenesis.
TLDR
Using cultured human cell lines maintained in a quiescent or slowly growing state in vitro, ATR was found to be activated following treatment with the common anti-cancer drug cisplatin in a manner dependent on the nucleotide excision repair (NER) system, suggesting that the excision gaps generated by NER may require a greater utilization of potentially mutagenic translesion synthesis polymerases in the absence of ATR kinase function. Expand
ATR addiction in multiple myeloma: synthetic lethal approaches exploiting established therapies.
TLDR
It is posited that adding an ATR inhibitor such as VX-970 to established therapeutic regimens may provide a remarkably broad benefit to myeloma patients and indicate that myel cancer cells extensively rely on ATR, but not on ATM, for DNA repair. Expand
Targeting ATR in cancer
TLDR
Insight is provided into the potential of targeting the replication stress response in cancer and the strategy of inhibiting ataxia telangiectasia and Rad3-related protein (ATR) and the need for reliable biomarkers to enable patient stratification are discussed. Expand
DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer.
TLDR
The data suggest that delayed repair of DSBs in NSCLC cells treated with CDDP-IR contributes to CDDP radiosensitization and that alterations of the DDR pathways by inhibition of specific DDR kinases can augment CD DP-IR cytotoxicity by a complementary mechanism. Expand
ATM and ATR as therapeutic targets in cancer.
TLDR
Preclinical data have provided a strong rationale for clinical testing of these compounds both in combination with radio- or chemotherapy, and in synthetic lethal approaches to treat tumours with deficiencies in certain DDR components, suggesting that a synthetic lethal approach with ATM or ATR inhibitors could have widespread utility, providing that appropriate biomarkers are developed. Expand
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