Journal ArticleDOI
Prexasertib, a checkpoint kinase inhibitor: from preclinical data to clinical development
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TLDR
The preclinical data and early clinical studies advocate the use of prexasertib in solid tumors both in monotherapy and in combination with other drugs (antimetabolites, PARP inhibitors and platinum-based chemotherapy); the safety and the efficacy of combination therapies with prex asertib need to be better evaluated in ongoing clinical trials.Abstract:
Checkpoint kinases 1 and 2 (CHK1 and CHK2) are important multifunctional proteins of the kinase family. Their main function is to regulate DNA replication and DNA damage response. If a cell is exposed to exogenous damage to its DNA, CHK1/CHK2 stops the cell cycle to give time to the cellular mechanisms to repair DNA breakage and apoptosis too, if the damage is not repairable to activate programmed cell death. CHK1/CHK2 plays a crucial role in the repair of recombination-mediated double-stranded DNA breaks. The other important functions performed by these proteins are the beginning of DNA replication, the stabilization of replication forks, the resolution of replication stress and the coordination of mitosis, even in the absence of exogenous DNA damage. Prexasertib (LY2606368) is a small ATP-competitive selective inhibitor of CHK1 and CHK2. In preclinical studies, prexasertib in monotherapy has shown to induce DNA damage and tumor cells apoptosis. The preclinical data and early clinical studies advocate the use of prexasertib in solid tumors both in monotherapy and in combination with other drugs (antimetabolites, PARP inhibitors and platinum-based chemotherapy). The safety and the efficacy of combination therapies with prexasertib need to be better evaluated in ongoing clinical trials.read more
Citations
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The Influence of Cell Cycle Regulation on Chemotherapy.
TL;DR: In this paper, the authors presented the mechanism of commonly used chemotherapeutic drugs and the effect of the cell cycle on tumorigenesis and development, and the interaction between chemotherapy and cell cycle regulation in cancer treatment was briefly introduced.
Journal ArticleDOI
Reality CHEK: Understanding the biology and clinical potential of CHK1.
TL;DR: The current understanding of the principal roles of CHK1 is expound and different avenues forCHK1 targeting in cancer therapy are highlighted.
Journal ArticleDOI
Targeting DNA Damage Response in Prostate and Breast Cancer.
TL;DR: The combination of anti-hormonal therapy with DDR inhibition or with radiation has the potential to enhance efficacy but still needs further investigation, and preclinical and clinical findings made in addressing DNA repair dysfunction in hormone-dependent and -independent prostate and breast tumors are presented.
Journal ArticleDOI
PARP Inhibitors for Ovarian Cancer: Current Indications, Future Combinations, and Novel Assets in Development to Target DNA Damage Repair
TL;DR: The current indications for PARPIs in both frontline and recurrent settings, current research in combination approaches, and ongoing research on novel methods to target DNA damage response are discussed in an effort to exploit the common susceptibility to DNA damage repair in epithelial ovarian cancer and improve outcomes for patients.
Journal ArticleDOI
Participation of the ATR/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer.
TL;DR: The use of DNA repair checkpoint inhibitors as single agents and strategies combining these inhibitors with DNA-damaging compounds for ovarian cancer therapy, as well as the new platforms used for optimizing ovarian cancer treatment are described.
References
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TL;DR: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.
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Michael B. Kastan,Jiri Bartek +1 more
TL;DR: All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation, and how cells respond to DNA damage are critical determinants of whether that individual will develop cancer.
Journal ArticleDOI
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Whole-genome characterization of chemoresistant ovarian cancer
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TL;DR: It is shown that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance.