LY2140023 is a novel investigational agent for the treatment of schizophrenia

by Selleckchem | Jan 18 2013

Triple-negative breast cancer lacks the expression of estrogen receptor , progesterone receptor , and human epidermal growth factor receptor 2 gene amplification and carries a particularly poor prognosis due to LY2140023 its association with aggressive tumor characteristics and the lack of effective targeted therapies. Interestingly, TP53 mutation is observed in up to 44% of TNBC compared with 15% in the more indolent ER-positive breast cancers . p53 plays a key role in arresting cell-cycle progression in the presence of genotoxic stress in order to maintain genome integrity. In response to DNA damage, normal cells arrest in G1 to MG-132 allow time for DNA repair or they proceed into apoptosis if the DNA damage is too severe. In contrast, p53-deficient tumor cells rely on checkpoint kinase 1 to arrest cell-cycle progression in the S and G2 phases. In response to replicative or genotoxic stress, Chk1 phosphorylates its key target, the Cdc25A phosphatase . This leads to ubiquitin-mediated proteolysis of Cdc25A and cell-cycle arrest . When the S and G2 checkpoints are abrogated by inhibition of Chk1, p53-deficient cancer cells undergo mitotic catastrophe and apoptosis .
Several preclinical studies have demonstrated that Chk1 inhibitors selectively MK-2866 potentiate the effects of DNA-damaging agents, such as chemotherapy or radiation, in TP53-mutated cancer cells, and several Chk1 inhibitors are being tested in clinical trials . Since TNBC is commonly associated with TP53 mutation, we hypothesized that a potential therapeutic strategy for treating TNBC would be to inhibit Chk1 to enhance the cytotoxicity of DNA-damaging agents. We tested this hypothesis by using 2 different Chk1 inhibitors . UCN-01 is a multitarget serine-threonine protein kinase inhibitor that potently inhibits Chk1 and was the first Chk1 inhibitor to be identified . UCN-01 exhibits preclinical synergy with DNA-damaging agents . AZD7762 is a newer generation, more selective Chk1 inhibitor. AZD7762 inhibits Chk1 by reversibly binding to the molecule library ATP-binding site of Chk1, with an IC50 of 5 nM and a KI of 3.6 nM . In this study, we tested the hypothesis that loss of p53 function would exhibit synthetic lethality with DNA damage and Chk1 inhibition in TNBC. We predicted that inhibition of Chk1 would enhance the antitumor effects of irinotecan by eliminating checkpoint responses selectively in tumors harboring TP53 mutations.
We employed early passage human-in-mouse models , which are patient tumor explants engrafted into the ??humanized?? mammary fat pads of immunocompromised mice. We denoted these HIM models as Washington University?Cbreast cancer tumor lines. Three TNBC HIM lines were chosen, 1 WT and 2 mutant for TP53. Mice engrafted with these tumors were treated with mTOR inhibition irinotecan and 2 different Chk1 inhibitors either as single agents or in combination for longterm survival and tumor growth studies as well as short-term pathway analysis. In addition, isogenic lines of WU-BC3 differing only in p53 status were generated, and the response of these lines to the combination of irinotecan and AZD7762 was assessed to determine the contribution made by p53 status to tumor response.