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Immunotherapy in Head and Neck Cancers
Published in R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne, Scott-Brown's Essential Otorhinolaryngology, 2022
Chk1 is directly downstream of ATR in the DNA damage response signalling cascade. Chk1 inhibitors that have been tested include UCN-01, AZD7762, and SAR-020106, but all of them had severe toxicities and lacked clinical efficacy.
Basic Science and Molecular Oncology
Published in Manit Arya, Taimur T. Shah, Jas S. Kalsi, Herman S. Fernando, Iqbal S. Shergill, Asif Muneer, Hashim U. Ahmed, MCQs for the FRCS(Urol) and Postgraduate Urology Examinations, 2020
Paul Cleaveland, Vijay Sangar, Noel Clarke
DNA damage causes a number of protein-protein interactions that alter protein phosphorylation. Initial sensing of damage is picked up by ATM and ATR proteins. These send signals to phosphorylate CHK2, CHK1, p53, MDM2 and BRCA1, which in turn arrest the cell cycle at checkpoints until DNA damage is repaired. The phosphorylation of p53 proteins causes altered activity in the CDK-inhibitor p21 WAF, which results in G1/S checkpoint arrest. S phase arrest results from phosphorylation of NBS1 and SMC1 directly via ATM. G2/mitosis arrest results from phosphorylation of CDC25C via CHK2 and CHK1.
CDK Inhibitors in Leukemia and Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
UCN-01 (7-hydroxystaurosporine, NSC638850 or KW-2401; Kyowa Hakka Kogyo Company Ltd., Tokyo, Japan), a derivative of the nonspecific PKC inhibitor staurosporine (a natural product isolated from Streptomyces staurosporeus), was originally developed as a selective PKC inhibitor. Studies have also reported that UCN-01 inhibits several CDKs. However, recent studies have shown that it exerts other antitumor effects, including inhibition of Chk1, which results in “inappropriate” activation of CDKs and abrogation of DNA damage-induced cell cycle checkpoints, as well as interference with the PDKl/Akt survival pathway, thus promoting induction of apoptosis. These effects are largely independent of PKC inhibition. UCN-01 displays antitumor activity in in vitro systems and in vivo xenograft models involving multiple human tumor types, with greater antitumor effects observed in longer administration intervals (e.g., 72 hours in in vitro systems) (23).
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
CHK1 is a key protein kinase in the ATR DNA damage signaling pathway at the S and G2-M checkpoints. The CHK2 kinase is located downstream in the ATM pathway and is mediated through p53 [59]. Because functional p53 is required for DNA repair through the ATM/CHK2 pathway, tumors with TP53 mutations have an increased reliance on CHK1 in the presence of DNA damage as ATM/CHK2 signaling is defective [59]. BRCA plays a role in homologous recombination in response to replication stress, so it would be expected that efficacy of CHK1 inhibition would be greater in BRCA mutant tumors due to higher levels of replication stress [60,61]. Prexasertib currently has the most clinical experience of the CHK1 inhibitors. Interestingly, much of the success of prexasertib has been in BRCA wildtype tumors. In a phase II trial in high grade serous ovarian cancer, prexasertib monotherapy had a relative response rate of 11% in patients with BRCA mutated tumors however, the relative response in patients with BRCA wild-type tumors was 33% [61–63]. Additionally, in a phase II study in nine patients with BRCA wild-type triple negative breast cancer, the overall response rate with single-agent prexasertib was 11% with 4 additional patients achieving stable disease [64].
Targeting DNA damage response in head and neck cancers through abrogation of cell cycle checkpoints
Published in International Journal of Radiation Biology, 2021
Jessica M. Molkentine, David P. Molkentine, Kathleen A. Bridges, Tongxin Xie, Liangpeng Yang, Aakash Sheth, Timothy P. Heffernan, David A. Clump, Alma Z. Faust, Robert L. Ferris, Jeffrey N. Myers, Mitchell J. Frederick, Kathryn A. Mason, Raymond E. Meyn, Curtis R. Pickering, Heath D. Skinner
HPV(+) cells express p16 which downregulates TRIP12 leading to reduced BRCA1 foci formation and reduced HR capacity (Wang, Zhang, et al. 2017). HPV(+) cells have also been shown to have higher levels of 53BP1 foci following radiation than HPV(−) cells indicative of a greater reliance on NHEJ (Wang, Wang, et al. 2017; Wang, Zhang, et al. 2017). However, in HPV(+) cells p53 is ubiquitinated and degraded due to E6 viral oncogene expression (Munger et al. 2004; Liu et al. 2018) which disrupts G1 arrest thus limiting their ability to perform NHEJ during G1 arrest (Kessis et al. 1993; Havre et al. 1995). Therefore, HPV(+) cells have limited DNA repair options and rely more heavily on S phase checkpoints or performing NHEJ outside of G1 than other non-HPV derived cancers. In addition to its role in DNA damage response in G2/M, Chk1 is also involved in maintenance of genome integrity through replication fork stabilization and plays a critical role in the intra-S-phase checkpoint (Bartek et al. 2004). With so few DDR options, interfering with S phase checkpoints by inhibition of Chk1 and PARP could lead to catastrophic genomic instability following radiation induced DNA damage in HPV(+) cancers.
Disposition of [14C]LY2606368 following intravenous administration in patients with advanced and/or metastatic solid tumours
Published in Xenobiotica, 2020
Enaksha R. Wickremsinhe, Scott M. Hynes, Christopher D. Payne, Yingying Guo, Kenneth C. Cassidy
LY2606368 (prexasertib) is a potent and selective adenosine triphosphate-competitive inhibitor of checkpoint kinase 1 (CHK1). CHK1 is a multifunctional protein kinase and regulator of cell cycle progression (Dai & Grant, 2010). In response to exogenous DNA damage, CHK1 mediates cell cycle arrest to allow time for DNA repair or if the damage is extensive, to trigger apoptosis. CHK1 affects the initiation of DNA replication origin firing, stabilisation of replication forks, resolution of replication stress, and coordination of mitosis, even in the absence of exogenous DNA damage (Mcneely et al., 2014). Thus, the inhibition of CHK1 by compounds such as prexasertib disrupts DNA replication, induces DNA damage, and subsequently prevents repair, leading eventually to death by mitotic catastrophe due to the presence of unresolved DNA breaks (King et al., 2015). Prexasertib has also exhibited an acceptable safety profile in both nonclinical toxicology studies (with monitorable and reversible effects), and a phase 1 clinical study when administered at the recommended phase 2 dose (RP2D) of 105 mg/m2 as a 1-h infusion to patients with advanced cancer (Hong et al., 2016, 2018; Lee et al., 2018).