MK-8776

Olaparib-resistant xenografts were treated with olaparib, ATR inhibitor (ATRi, ceralasertib), CHK1 inhibitor (CHK1i, MK-8776) or their combinations. Our collective findings indicate that ATR/CHK1 pathway inhibition restores the olaparib efficacy in resistant BRCA1/2MUT high-grade serous OC, highlighting promising approach for olaparib rechallenge of non-responsive patients. Uncovered mechanisms might improve our understanding of acquisition and overcoming resistance to olaparib in ovarian cancer.

Loss of FAM110C expression sensitizes PDAC cells to VE-822 (an ATR inhibitor) and MK-8776 (a CHK1 inhibitor). FAM110C methylation is a potential diagnostic and prognostic marker in PDAC, and its epigenetic silencing sensitizes PDAC cells to ATR/CHK1 inhibitors.

HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier. Collectively, our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H, providing a potential therapeutic approach for the treatment of TNBC.

Through in silico screening of 2183 drug targets and 1646 compounds, we identified two targets (RRM2 and OPRD1) and eight agents (AZ960, carmustine, lasalocid, SGI-1776, AZD8055_1059, BPD.00008900_1998, MK.8776_2046, and XAV939_1268) with potential therapeutic implications for high-MRPScore patients. Indeed, a high MRPScore profile appears to elevate the risk of tumor progression and mortality, potentially through its influence on immune regulation. This suggests that the MRPS-related risk model holds promise as a prognostic predictor and may offer novel insights into personalized therapeutic strategies.

Here we newly demonstrate that pharmacological inhibition of Chk1 using potent and selective inhibitor SCH900776, currently profiled in phase II clinical trials, significantly enhances cytotoxic effects of the combination of platinum-based drugs (cisplatin or LA-12) and TRAIL (tumor necrosis factor-related apoptosis inducing ligand) in human prostate cancer cells. The triple drug combination-induced cytotoxicity was partially enhanced by siRNA-mediated Mcl-1 silencing. Our findings suggest that targeting Chk1 may be used as an efficient strategy for sensitization of prostate cancer cells to killing action of platinum-based chemotherapeutic drugs and TRAIL.

Importantly, targeted inhibition of the check-point inhibitor CHK1 with MK-8776 effectively caused death of p21-high T47D cells, thus establishing a new vulnerability of BYL719-resistant breast cancer cells. Together, our integrated studies uncover hidden molecular mediators causing resistance to PI3Kα inhibition and provide a framework to prioritize combination therapies for PI3K-mutant breast cancer.

Antitumor activity of olaparib alone or combined with an ATR inhibitor (ATRi, ceralasertib) or CHK1 inhibitor (CHK1i, MK-8776) was evaluated in OC cell lines sensitive (PEO1, PEO4) and resistant (PEO1-OR) to olaparib. Overall, the addition of ATRi or CHK1i to olaparib effectively overcomes resistance to PARPi exerting anti-proliferative effect in BRCA2 olaparib-resistant OC cells and alters expression of DDR-related proteins. These new molecular insights into cellular response to olaparib combined with ATR/CHK1 inhibitors might help improve targeted therapies for olaparib-resistant OC.

We classified 3 molecular subtypes for HNSC patients and established an ARS prognostic model, which offered a prospective direction for prognosis in HNSC.

The current treatment approach for APL involves differentiation therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Overall, the ability of MK-8776 to induce PML-RARα degradation and stimulate differentiation of immature APL cancer cells into more mature forms recapitulates the concept of differentiation therapy. Considering the in vivo tolerability of MK-8776, it will be relevant to evaluate its potential clinical benefit in APL patients resistant to standard ATRA/ATO therapy, as well as in patients with other forms of acute leukemias.

Different TNBC cell lines were treated with AURKA inhibitor (AURKAi, MLN8237) and CHK1i (CHK1i, MK8776). Additionally, dual inhibition of AURKA and CHK1 synergistically enhanced radiosensitivity in MDA-MB-231 xenografts. Moreover, we detected that both CHEK1 and AURKA were overexpressed in TNBC patients and negatively correlated with patients' survival Our findings suggested that AURKAi in combination with CHK1i enhanced TNBC radiosensitivity in preclinical models, potentially providing a novel strategy of precision treatment for patients with TNBC.

Combining olaparib with ATR/CHK1 inhibitors increases its effectiveness and may be a new opportunity for more effective ovarian cancer therapy.Material and MethodsWe examined efficacy of PARPi in combination with DNA damage response pathway proteins inhibitors - ATR (AZD6738, ATRi) and CHK1(MK8776, CHK1i) kinases in BRCAMUT (PEO-1) and BRCAWT (SKOV-3 and OV-90) cells. ATR and CHK1 inhibitors provoke premature mitotic entry, leading to genomic instability and ultimately cell death. This research was funded by the National Science Centre, Poland, grant number: Sonata Bis 2019/34/E/NZ7/00056.

The anticancer activity and action of olaparib combined with inhibitors of the ATR/CHK1 pathway (ceralasertib as ATRi, MK-8776 as CHK1i) in olaparib-sensitive and -resistant OC cell lines were evaluated. Collectively, olaparib-resistant cells display co-existing HR repair-related mechanisms that confer resistance to olaparib, which may be effectively utilized to resensitize them to PARPi via combination therapy. Importantly, the addition of ATR/CHK1 pathway inhibitors to olaparib has the potential to overcome acquired resistance to PARPi.

High-ENZ-sig patients were more sensitive to cell cycle-targeted drugs (MK-1775, AZD7762, and MK-8776) than low-ENZ-sig patients in PCa. Our results provided evidence and insight on the potential utility of ENZ-sig in PCa prognosis and combination therapy strategy of enzalutamide and cell cycle-targeted compounds in treating PCa.

Mice models for NB and MB were treated with vehicle, PARPi olaparib (50 mg/kg), CHK1i MK-8776 (25 mg/kg) or their combination and tumor growth was measured by caliper or bio-luminescent imaging. Furthermore, emerging evidence indicates that enhanced RS plays a central role in the activation of immune response (IR) and could serve as a predictive marker for immunotherapy. Since PARPi have been linked to modulation of IR, it is possible that additional benefits may be obtained by PARPi+CHK1i in immunocompetent mouse models.

CHK1 could be considered as an appealing novel pharmacological target for the treatment of luminal primary and MBCs.

Suboptimal doses of the CHK1 inhibitor MK-8776 plus the PARP inhibitor olaparib led to a MYCN-dependent accumulation of DNA damage and cell death in vitro and significantly reduced the growth of four in vivo models of MYCN-driven tumors, without major toxicities. Our data highlight the combination of PARP and CHK1 inhibitors as a new potential chemo-free strategy to treat MYCN-driven tumors, which might be promptly translated into clinical trials.

IMR32 were xenografted in nude mice, which were treated with vehicle, olaparib (50 mg/kg), CHK inhibitor (CHK1i) MK-8776 (25 mg/kg) or their combination. Conclusion In conclusions, our data highlight a new potential chemo-free strategy to treat MNA NB. Moreover, they shed light on the involvement of ATM kinase in shaping NB cell responses to PARPi+CHK1i depending on their genetic background.

IMR32 were xenografted in nude mice, which were treated with vehicle, olaparib (50 mg/kg), CHK inhibitor (CHK1i) MK-8776 (25 mg/kg) or their combination. Conclusion In conclusions, our data highlight a new potential chemo-free strategy to treat MNA NB. Moreover, they shed light on the involvement of ATM kinase in shaping NB cell responses to PARPi+CHK1i depending on their genetic background.

IMR32 were xenografted in nude mice, which were treated with vehicle, olaparib (50 mg/kg), CHK inhibitor (CHK1i) MK-8776 (25 mg/kg) or their combination. Conclusion In conclusions, our data highlight a new potential chemo-free strategy to treat MNA NB. Moreover, they shed light on the involvement of ATM kinase in shaping NB cell responses to PARPi+CHK1i depending on their genetic background.

IMR32 were xenografted in nude mice, which were treated with vehicle, olaparib (50 mg/kg), CHK inhibitor (CHK1i) MK-8776 (25 mg/kg) or their combination. Conclusion In conclusions, our data highlight a new potential chemo-free strategy to treat MNA NB. Moreover, they shed light on the involvement of ATM kinase in shaping NB cell responses to PARPi+CHK1i depending on their genetic background.

Our study demonstrates that MK-8776 and gemcitabine combined induces apoptosis and suppresses proliferation in bladder cancer cells by inhibiting CHKs and DNA repair. Therefore, CHK1 inhibition combined with gemcitabine may be a potential treatment for bladder cancer.

Here, we evaluated the effect of olaparib, the ATR inhibitor AZD6738, and the CHK1 inhibitor MK8776 alone and in combination on cell survival, colony formation, replication stress response (RSR) protein expression, DNA damage, and apoptotic changes in BRCA2 mutated (PEO-1) and HRR-proficient BRCA wild-type (SKOV-3 and OV-90) cells. Because PARPi increases the reliance on ATR/CHK1 for genome stability, the combination of PARPi with ATR inhibition suppressed ovarian cancer cell growth independently of the efficacy of HRR. The present results were obtained at sub-lethal doses, suggesting the potential of these inhibitors as monotherapy as well as in combination with olaparib.

We found that suppression of H3.3S31ph by CHK1 inhibitor MK-8776 sensitizes the CLL-like line MEC1 to EZH1/2 inhibition (Fig...We then showed that an EZH2 inhibitor, Valemetostat, reduce the survival of the primary CLL B-cells (Fig... In summary, we have elucidated how epigenetic features in leukemic CLL B-cells (H3K27me3 and H3.3S31ph), can provide novel treatment targets for CLL (Fig. 1 I). Moreover, this study may provide a proof of concept to develop new treatment strategies based on epigenetic vulnerabilities in other hematological malignancies.

Moreover, in a mouse model of FLT3/ITD acute myeloid leukemia, treatment with the CHK1 inhibitor MK8776 + cytarabine extended survival over cytarabine alone. These findings suggest that FLT3/ITD and Rac1 activity cooperatively modulate DNA repair activity, the addition of DNA damage response inhibitors to conventional chemotherapy may be useful in the treatment of FLT3/ITD acute myeloid leukemia, and inhibition of the Rac signaling pathways via DOCK2 may provide a novel and promising therapeutic target for FLT3/ITD acute myeloid leukemia.

The Chk1 inhibitor MK-8776 was most effective, reducing viral DNA amplification by 90-99% and caused DNA damage and apoptosis, preferentially in HPV infected cells. Furthermore, it sensitized the cells to cisplatin, commonly used to treat advanced cervical cancer. Based on these observations, the Chk1 inhibitors could be potential effective agents to be re-purposed to treat the spectrum of HPV infections in single or combination therapy.

Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant BRCA1 mutated OC cell models, and are rationale combinations for further clinical development.

HPV status also plays a role in response to MK-8776 or MK-1775 when combined with niraparib due to differences in DNA repair mechanisms. This study suggests that using cell cycle abrogators in combination with PARP inhibitors may be a beneficial treatment option in HNSCC, but also emphasizes the importance of HPV status when considering effective treatment strategies.