Human cells have three CDC25 proteins that control cell cycle changes by eliminating the inhibitory phosphorylation from cyclin dependent kinases. p53 plays a key role in arresting cell cycle progression in the existence of genotoxic stress to be able to retain price Decitabine genome integrity. In reaction to DNA damage, typical cells arrest in G1 to permit time for DNA repair or if the DNA damage is too severe they continue into apoptosis. In contrast, p53 deficient tumefaction cells rely on checkpoint kinase 1 to arrest cell cycle progression in the S and G2 phases. In a reaction to replicative or genotoxic tension, Chk1 phosphorylates its key goal, the phosphatase. This results in ubiquitin mediated proteolysis of Cdc25A and cell cycle arrest. When the S and G2 check-points are abrogated by inhibition of Chk1, p53 deficient cancer cells undergo mitotic devastation and apoptosis. Several preclinical studies have demonstrated that Chk1 inhibitors selectively potentiate the effects of DNA damaging agents, such as for example chemotherapy or radiation, in TP53 mutated cancer cells, and several Chk1 inhibitors are being tested in clinical studies. We hypothesized that Cholangiocarcinoma a potential therapeutic strategy for treating TNBC should be to prevent Chk1 to enhance the cytotoxicity of DNA damaging agents, since TNBC is usually associated with TP53 mutation. 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 very first Chk1 inhibitor to become determined. UCN 01 exhibits preclinical synergy with DNA damaging agents. AZD7762 is just a newer generation, more selective Chk1 inhibitor. AZD7762 checks Chk1 by reversibly binding to the ATP binding site of Chk1, with an IC50 of 5 nM and a KI of 3. 6 nM. In this study, we examined the hypothesis that loss in p53 function would display synthetic lethality with Chk1 inhibition and DNA damage in TNBC. We expected that inhibition of Chk1 could improve the anti-tumor effects of irinotecan by detatching Bicalutamide clinical trial checkpoint responses selectively in tumors harboring TP53 mutations. We used early passage human in mouse models, which are patient tumor explants engrafted in to the humanized mammary fat pads of immunocompromised mice. We denoted these HIM models as Washington University breast cancer tumefaction lines. Three TNBC HIM lines were plumped for, 2 and 1 WT mutant for TP53. Rats engrafted with these tumors were treated with irinotecan and 2 different Chk1 inhibitors both as single agents or in combination for long haul survival and tumor growth studies as well as short-term path analysis. Furthermore, isogenic lines of WU BC3 differing only in p53 status were generated, and the response of those lines to the mix of irinotecan and AZD7762 was considered to determine the contribution made by p53 status to tumor response. Results Generation of HIM cyst types of TNBC. We used methods first explained by Kuperwasser et al. to establish a panel of HIM breast cancer xenograft types in immunodeficient NOD/ SCID mice.