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    GENE:

    CHEK1 (Checkpoint kinase 1)

    i
    Other names: CHEK1, CHK1, Checkpoint kinase 1
    1d
    p53 pathway genes’ mutations (muts) as prognostic factors in patients (pts) with metastatic Pancreatic Ductal Adenocarcinoma (mPDAC): a single center study (AIOM 2024)
    Our study suggests an important prognostic role of p53 signaling muts in mPDAC pts; wt pts resulted in a longer OS than mutated pts, although some muts, in particular tp53 exon4 mut, seem to be associated with longer survival. Further studies are needed to investigate these findings, including an in-depth analysis of structural proteomics.
    Clinical • Metastases
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    KRAS (KRAS proto-oncogene GTPase) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • CHEK2 (Checkpoint kinase 2) • MDM4 (The mouse double minute 4) • CHEK1 (Checkpoint kinase 1) • TP53BP1 (Tumor Protein P53 Binding Protein 1)
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    TP53 mutation • KRAS mutation • TP53 wild-type • TP53 exon 4 mutation
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    TruSight Oncology 500 Assay
    1d
    Homologous recombination (HR) and DNA damage repair (DDR) somatic alterations in metastatic colorectal cancer (mCRC): results from the comprehensive genomic profiling (CGP) trial FPG500 (AIOM 2024)
    Background : Treatment (tx) of MSS/MMRp mCRC relies mainly on oxaliplatin (oxa)- or irinotecan-based doublet chemotherapy regimens, with no biomarker reported so far, allowing the selection of one tx over the other. HR-DDRa is associated with MSI-H or TMB-H. Pts with MSS HR-DDRa tumors benefit from oxa-based first line treatment. Longer FU, allowing mature OS data, and wider cohorts are warranted.
    Tumor mutational burden • BRCA Biomarker • MSi-H Biomarker • Metastases
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    TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • BAP1 (BRCA1 Associated Protein 1) • PALB2 (Partner and localizer of BRCA2) • ATRX (ATRX Chromatin Remodeler) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD50 (RAD50 Double Strand Break Repair Protein) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • MRE11A (MRE11 homolog, double strand break repair nuclease) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • FANCL (FA Complementation Group L) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCC (FA Complementation Group C)
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    TMB-H • MSI-H/dMMR
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    TruSight Oncology 500 Assay
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    oxaliplatin • irinotecan
    2d
    Inhibition of Chk1 with Prexasertib Enhances the Anticancer Activity of Ciclopirox in Non-Small Cell Lung Cancer Cells. (PubMed, Cells)
    This was associated with increased expression of DR4, DR5, Fas, and FADD and decreased expression of survivin, resulting in activation of caspase 8 and caspase 3 as well as cleavage of poly (ADP ribose) polymerase (PARP). Taken together, the results suggest that inhibition of Chk1 with PRE can enhance the anticancer activity of CPX at least partly by decreasing cell proliferation and increasing apoptosis in NSCLC cells.
    Journal • PARP Biomarker
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    CDK4 (Cyclin-dependent kinase 4) • BIRC5 (Baculoviral IAP repeat containing 5) • CDK6 (Cyclin-dependent kinase 6) • CHEK1 (Checkpoint kinase 1) • FADD (Fas associated via death domain) • CASP3 (Caspase 3) • CASP8 (Caspase 8) • CDK2 (Cyclin-dependent kinase 2) • CDC25C (Cell Division Cycle 25C) • CDC25B (Cell Division Cycle 25B) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1)
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    BIRC5 expression
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    prexasertib (ACR-368)
    2d
    PARylation of GCN5 by PARP1 mediates its recruitment to DSBs and facilitates both HR and NHEJ Repair. (PubMed, Cell Mol Life Sci)
    Together, this study identifies an untraversed DSB repair function of GCN5 and provides mechanistic insights into transcriptional as well as post-translational regulation of pivotal HR-NHEJ factors. Alongside, it highlights the translational importance of PARP1-GCN5 axis in mediating GBM radio-resistance.
    Journal
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    BRCA1 (Breast cancer 1, early onset) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • CHEK1 (Checkpoint kinase 1) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit) • TP53BP1 (Tumor Protein P53 Binding Protein 1)
    3d
    Panobinostat Synergizes with Chemotherapeutic Agents and Improves Efficacy of Standard-of-Care Chemotherapy Combinations in Ewing Sarcoma Cells. (PubMed, Cancers (Basel))
    The combination of Panobinostat with Doxorubicin or Etoposide, both of which are used as standard of care in upfront treatment, leads to a synergistic effect in EWS cells. Overall, our data indicate that HDAC2 is overexpressed in many EWS tumor samples and HDAC inhibition is effective in targeting EWS cells, alone and in combination with standard-of-care chemotherapy agents. This work suggests that the addition of an HDAC inhibitor to upfront treatment may improve response.
    Journal
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    ALK (Anaplastic lymphoma kinase) • CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4) • CHEK2 (Checkpoint kinase 2) • JAK1 (Janus Kinase 1) • CHEK1 (Checkpoint kinase 1) • CASP3 (Caspase 3) • HDAC2 (Histone deacetylase 2)
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    CCND1 expression • HDAC2 expression
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    doxorubicin hydrochloride • etoposide IV • Farydak (panobinostat)
    3d
    Discovery of key molecular signatures for diagnosis and therapies of glioblastoma by combining supervised and unsupervised learning approaches. (PubMed, Sci Rep)
    Finally, we recommended KGs-guided four repurposable drug molecules (Fluoxetine, Vatalanib, TGX221 and RO3306) against GBM through molecular docking, drug likeness, ADMET analyses and molecular dynamics simulation studies. Thus, the discoveries of this study could serve as valuable resources for wet-lab experiments in order to take a proper treatment plan against GBM.
    Journal
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    TOP2A (DNA topoisomerase 2-alpha) • RAD51 (RAD51 Homolog A) • AURKA (Aurora kinase A) • CHEK1 (Checkpoint kinase 1) • RAD51AP1 (RAD51 Associated Protein 1) • CCNB2 (Cyclin B2) • CDK1 (Cyclin-dependent kinase 1) • MCM10 (Minichromosome Maintenance 10 Replication Initiation Factor) • CDCA8 (Cell Division Cycle Associated 8)
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    TGX-221 • fluoxetine • vatalanib (PTK787)
    14d
    Targeting the DNA damage response in cancer. (PubMed, MedComm (2020))
    In parallel, the search for synthetic lethality interaction is broadening the use of DDR inhibitors. In this review, we discuss the state-of-art of ataxia-telangiectasia mutated, ataxia-telangiectasia-and-Rad3-related protein, checkpoint kinase 1, Wee1 and Polθ inhibitors, highlighting the results obtained in the ongoing clinical trials both in monotherapy and in combination with chemotherapy and radiotherapy.
    Review • Journal
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    ATR (Ataxia telangiectasia and Rad3-related protein) • CHEK1 (Checkpoint kinase 1)
    18d
    Chidamide Combined with (+) -JQ-1 to Kill MLL-Rearrangement Acute Myeloid Leukemia Cells by Disrupting the DNA Damage Response Pathway (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi)
    Chidamide combined with (+)-JQ-1 can inhibit the proliferation of MLL-r AML cells, inhibit the initiation of protective self-repair of these leukemia cells by inhibiting the DNA damage response pathway, and ultimately increase the apoptosis of these cells, but non- MLL-r AML cells have no similar results.
    Journal • IO biomarker
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    BCL2 (B-cell CLL/lymphoma 2) • KMT2A (Lysine Methyltransferase 2A) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • CHEK1 (Checkpoint kinase 1) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • BRD4 (Bromodomain Containing 4) • TP53BP1 (Tumor Protein P53 Binding Protein 1)
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    MLL rearrangement • MLL rearrangement • BCL2 expression • BAX expression
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    JQ-1 • Epidaza (chidamide)
    19d
    Potential Therapeutic Targets in Triple-Negative Breast Cancer Based on Gene Regulatory Network Analysis: A Comprehensive Systems Biology Approach. (PubMed, Int J Breast Cancer)
    The overexpression of CHEK1 and PLK1 in TNBC compared to non-TNBC samples was validated by expression analysis. This study provides insights into the molecular mechanisms of TNBC and suggests CHEK1, PLK1, and their upstream regulators as potential therapeutic targets for TNBC treatment.
    Journal
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    PLK1 (Polo Like Kinase 1) • CHEK1 (Checkpoint kinase 1)
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    CHEK1 overexpression
    24d
    A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors. (PubMed, Clin Cancer Res)
    Across cohorts, only SDH-mutant GIST patients experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.
    Journal • Metastases
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    ATM (ATM serine/threonine kinase) • SLFN11 (Schlafen Family Member 11) • ATRX (ATRX Chromatin Remodeler) • CHEK1 (Checkpoint kinase 1)
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    ATM mutation • ATRX mutation
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    berzosertib (M6620)
    26d
    Exploration of the carcinogenetic and immune role of CHK1 in human cancer. (PubMed, J Cancer)
    CHK1 was highly expressed in multiple cancers and was related to clinical stage, survival, immune infiltration in pan-cancers. Our study found that CHK1 was significantly related to prognosis and immunological status in various cancers, suggesting that CHK1 may serve as a useful biomarker for prognosis and immune infiltration in cancer.
    Journal
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    CHEK1 (Checkpoint kinase 1)
    1m
    Inflammasome protein scaffolds the DNA damage complex during tumor development. (PubMed, Nat Immunol)
    Genotoxicity-induced activation of the NLRC4-ATR-ATRIP-ETAA1 complex drove the tumor-suppressing DNA damage response and CHK1 activation, and further attenuated the accumulation of DNA damage. These findings demonstrate a noninflammatory function of an inflammasome protein in promoting the DNA damage response and mediating protection against cancer.
    Journal
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    ATR (Ataxia telangiectasia and Rad3-related protein) • CHEK1 (Checkpoint kinase 1) • AIM2 (Absent In Melanoma 2) • NLRP6 (NLR Family Pyrin Domain Containing 6) • NLRP3 (NLR Family Pyrin Domain Containing 3)
    1m
    Crispr-mediated genome editing reveals a preponderance of non-oncogene addictions as targetable vulnerabilities in pleural mesothelioma. (PubMed, Lung Cancer)
    By integrating genomic analysis with a series of in vitro and in vivo functional studies, we validate and prioritize several non-oncogene addictions conferred by CDK7, CHK1, HDAC3, RAD51, TPX2, and UBA1 as targetable vulnerabilities, revealing previously unappreciated aspects of PM biology. Our findings support the growing consensus that stress-responsive non-oncogenic signaling plays a key role in the initiation and progression of PM and provide a functional blueprint for the development of unprecedented targeted therapies to combat this formidable disease.
    Journal
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    RAD51 (RAD51 Homolog A) • CHEK1 (Checkpoint kinase 1) • CDK7 (Cyclin Dependent Kinase 7) • HDAC3 (Histone Deacetylase 3)
    1m
    Proapoptotic activity of JNK-sensitive BH3-only proteins underpins ovarian cancer response to replication checkpoint inhibitors. (PubMed, Mol Cancer)
    Activation of the same signaling pathway occurs in HGSOC PDXs that are resistant to poly(ADP-ribose) polymerase inhibitors but respond to RCMs ex vivo with a decrease in cell number in 3-dimensional culture and in vivo with xenograft shrinkage or a significantly diminished growth rate. These findings identify key cell death-initiating events that link replication checkpoint inhibition to antitumor response in ovarian cancer.
    Journal • Checkpoint inhibition
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    BCL2L11 (BCL2 Like 11) • CHEK1 (Checkpoint kinase 1) • CDK2 (Cyclin-dependent kinase 2) • BBC3 (BCL2 Binding Component 3) • CDC25A (Cell Division Cycle 25A) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1)
    1m
    Advancing cancer therapy: new frontiers in targeting DNA damage response. (PubMed, Front Pharmacol)
    The development of PARP inhibitors like Olaparib has significantly improved the treatment of cancers with DDR defects (e.g., BRCA1 or BRCA2 mutations) based on synthetic lethality...Current research is focused on optimizing these therapies by developing predictive biomarkers for treatment response, analyzing mechanisms of resistance (both intrinsic and acquired), and exploring the potential for combining DDR-targeted therapies with chemotherapy, radiotherapy, and immunotherapy. This article provides an overview of the latest advancements in targeted anti-tumor therapies based on DDR and their implications for future cancer treatment strategies.
    Review • Journal • BRCA Biomarker • PARP Biomarker • IO biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)
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    BRCA2 mutation • BRCA1 mutation
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    Lynparza (olaparib)
    2ms
    Harnessing the synergy of nanosecond high-power microwave pulses and cisplatin to increase the induction of apoptosis in cancer cells through the activation of ATR/ATM and intrinsic pathways. (PubMed, Free Radic Biol Med)
    The obtained results elucidate the cellular mechanisms driving cell apoptosis/death, offering insights for potential advancements in cancer therapy through the combined application of nanosecond pulses of HPM and cisplatin. This serves as a first step for future investigations in this domain.
    Journal
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    BCL2 (B-cell CLL/lymphoma 2) • CHEK2 (Checkpoint kinase 2) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • CHEK1 (Checkpoint kinase 1) • CASP3 (Caspase 3) • CASP8 (Caspase 8)
    2ms
    Isovalerylspiramycin I suppresses small cell lung cancer proliferation via ATR/CHK1 mediated DNA damage response and PERK/eIF2α/ATF4/CHOP mediated ER stress. (PubMed, Biochem Pharmacol)
    Additionally, network pharmacology analysis, combined with cellular thermal shift assay (CETSA) and cycloheximide (CHX) chase experiments, demonstrated that ISP-I acted as a ligand for apurinic/apyrimidinic endonuclease 1 (APEX1) and promoted its degradation, leading to the accumulation of ROS. In conclusion, our findings elucidate the multifaceted mechanisms underlying the anti-cancer effects of ISP-I, highlighting its potential as a promising therapeutic candidate for SCLC treatment.
    Journal
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    CHEK1 (Checkpoint kinase 1) • HMGB1 (High Mobility Group Box 1) • CALR (Calreticulin) • ATF4 (Activating Transcription Factor 4) • APEX1 (Apurinic/Apyrimidinic Endodeoxyribonuclease 1)
    2ms
    DDB2 expression lights the way for precision radiotherapy response in PDAC cells, with or without olaparib. (PubMed, Cell Death Discov)
    Furthermore, DDB2 represents a significant step forward in precision radiotherapy by widening the scope of patients who can be benefiting from olaparib as a radiosensitizer. Hence, this research has the potential to enrich the limited use of radiotherapy in the care of patients with PDAC.
    Journal • BRCA Biomarker • PARP Biomarker
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1) • DDB2 (Damage Specific DNA Binding Protein 2)
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    Lynparza (olaparib)
    2ms
    CHANGEABLE: Combination of HX008 And Niraparib in GErm-line-mutAted Metastatic Breast Cancer (clinicaltrials.gov)
    P2, N=37, Completed, Fudan University | Recruiting --> Completed
    Trial completion • Metastases
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    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • BAP1 (BRCA1 Associated Protein 1) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD50 (RAD50 Double Strand Break Repair Protein) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • FANCF (FA complementation group F) • WRN (WRN RecQ Like Helicase) • FANCM (FA Complementation Group M) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCC (FA Complementation Group C)
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    HER-2 positive • BRCA2 mutation • BRCA1 mutation • HR positive • HER-2 negative • ATM mutation • PALB2 mutation • CDK12 mutation • BAP1 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • FANCA mutation • HR positive + HER-2 negative • RAD50 mutation • BARD1 mutation • BLM mutation • CHEK1 mutation • FANCF mutation • MRE11A mutation • NBN mutation • FANCM mutation • PTEN mutation + HR positive • CHEK1 expression • HER-2 negative + HR positive + BRCA mutation
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    Herceptin (trastuzumab) • Zejula (niraparib) • Puyouheng (pucotenlimab)
    2ms
    The anticancer effects of Aronia berry extract are mediated by Chk1 and p53 in colorectal cancer. (PubMed, Phytomedicine)
    We firstly provide evidence for the role of the p53 signaling pathway as a mediator of the anti-cancer activity of ABE, which provides a rationale for its use as a safe and effective integrative medicine approach in CRC.
    Journal
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    CHEK1 (Checkpoint kinase 1)
    2ms
    MiR-424-5p suppresses tumor growth and progression by directly targeting CHEK1 and activating cell cycle pathway in Hepatocellular Carcinoma. (PubMed, Heliyon)
    The present study demonstrates that miR-424-5p exerts a suppressive effect on HCC cell proliferation, migration, and invasion by downregulating the expression of CHEK1. This finding may offer a theoretical foundation for improving the prognosis and developing novel therapeutic strategies for HCC patients.
    Journal
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    CHEK1 (Checkpoint kinase 1) • MIR424 (MicroRNA 424)
    2ms
    Clinicopathological characteristics and genetic features of young and senior Ewing sarcoma patients. (PubMed, Diagn Pathol)
    Clinicopathological characteristics and genetic features in young and senior EwS patients differed significantly. Targeting cell cycle dysregulation based on age subgroup may be a potential therapeutic strategy for Ewing sarcoma.
    Journal
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    CCND1 (Cyclin D1) • CDK4 (Cyclin-dependent kinase 4) • EWSR1 (EWS RNA Binding Protein 1) • STAG2 (Stromal Antigen 2) • ERG (ETS Transcription Factor ERG) • CHEK1 (Checkpoint kinase 1) • EPHA3 (EPH receptor A3) • FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor) • SLIT2 (Slit Guidance Ligand 2)
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    CCND1 amplification • CDK4 amplification • STAG2 mutation • CCND1 expression • EWSR1-FLI1 fusion • CCND1-H • EPHA3 mutation • CHEK1 expression
    2ms
    AXL inhibition prevents RPA2/CHK1-mediated homologous recombination to increase PARP inhibitor sensitivity in hepatocellular carcinoma. (PubMed, Heliyon)
    AXL knockdown or AXL inhibition by bemcentinib reduces HR efficiency in HCC cells, and AXL plays its role in HR repair through its kinase activity...Mechanistically, AXL promotes the tyrosinization of RPA2 at tyrosine 9, promoting the phosphorylation of CHK1, thereby strengthens the HR repair ability in HCC cells to resist DNA damage. In conclusion, our results reveal that AXL is a promising therapeutic biomarker for HCC patients, and present that targeting AXL-RPA2-CHK1 pathway together with PARP inhibitor will be effective therapeutic strategy in HCC.
    Journal • PARP Biomarker
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    CHEK1 (Checkpoint kinase 1) • RPA2 (Replication Protein A2)
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    bemcentinib (BGB324)
    2ms
    Bone Marrow Stromal Cells Enhance Differentiation of Acute Myeloid Leukemia Induced by Pyrimidine Synthesis Inhibitors. (PubMed, Am J Physiol Cell Physiol)
    Human stromal cell lines HS-5 and HS-27, as well as primary MSCs isolated from patient bone marrow, were superior in promoting AML differentiation compared to mouse cells in response to AICAr and brequinar, with the inhibitors not significantly affecting the stromal cells themselves. In conclusion, our study highlights the supportive role of human BM MSCs in enhancing the differentiation effects of pyrimidine synthesis inhibitors on AML cells, suggesting that AML treatment strategies focusing on differentiation rather than cell killing may be successful in clinical settings.
    Journal • Stroma
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    CHEK1 (Checkpoint kinase 1)
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    brequinar (DUP 785)
    2ms
    14-3-3ε augments OGT stability by binding with S20-phosphorylated OGT. (PubMed, J Biol Chem)
    Moreover, we studied the R17C and S20A mutations in xenograft models and demonstrated that they both inhibit uterine carcinoma compared to wild-type OGT, probably due to less cellular reproduction. Our work is a sequel of our previous report on pS20 of OGT and is in line with the notion that OGT is intricately regulated by the mitotic network.
    Journal
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    CHEK1 (Checkpoint kinase 1) • VIM (Vimentin) • OGT (O-linked N-acetylglucosamine (GlcNAc) transferase)
    2ms
    Ovatodiolide Inhibits Endometrial Cancer Stemness via Reactive Oxygen Species-Mediated DNA Damage and Cell Cycle Arrest. (PubMed, Chem Biol Interact)
    It also suppressed the activation of mechanistic target of rapamycin kinase (mTOR) and nuclear factor kappa B (NF-κB) and downregulated glutathione peroxidase 1 (GPX1), an antioxidant enzyme counteracting oxidative stress...The ROS inhibitor N-acetylcysteine attenuated the anti-proliferative and anti-CSC effects of OVA. Our findings suggest that OVA acts via ROS generation, leading to oxidative stress and DNA damage, culminating in cell cycle arrest and the suppression of CSC activity in EC. Therefore, OVA is a promising therapeutic agent for EC, either as a standalone treatment or an adjunct to existing therapies.
    Journal
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    mTOR (Mechanistic target of rapamycin kinase) • CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1) • POU5F1 (POU Class 5 Homeobox 1) • CDK2 (Cyclin-dependent kinase 2) • CDC25C (Cell Division Cycle 25C) • CDK1 (Cyclin-dependent kinase 1) • NANOG (Nanog Homeobox) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1) • TCF4 (Transcription Factor 4)
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    sirolimus
    2ms
    The Potential for Targeting G2/M Cell Cycle Checkpoint Kinases in Enhancing the Efficacy of Radiotherapy. (PubMed, Cancers (Basel))
    Therefore, targeting the G2/M checkpoint through specific inhibitors is considered an important strategy for enhancing the efficacy of radiotherapy. In this review, we focus on inhibitors of Chk1 and Wee1 kinases and present the current biological evidence supporting their utility as radiosensitisers with different radiotherapy modalities, as well as clinical trials that have and are investigating their potential for cancer patient benefit.
    Review • Journal
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    TP53 (Tumor protein P53) • CHEK1 (Checkpoint kinase 1)
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    TP53 mutation • ATM mutation
    2ms
    Construction of thyroid cancer classification and iodine metabolism related diagnostic model using thyroid differentiation score and bioinformation. (PubMed, Medicine (Baltimore))
    Finally, the results of qRT-PCR corresponded with bioinformatics results. This diagnostic model has good diagnostic and prognostic value for THCA patients, and can be used as an independent prognostic indicator for THCA patients.
    Journal
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    CHEK1 (Checkpoint kinase 1)
    2ms
    DNA Damage-Inducing 10-Methoxy-canthin-6-one (Mtx-C) Promotes Cell Cycle Arrest in G2/M and Myeloid Differentiation of Acute Myeloid Leukemias and Leukemic Stem Cells. (PubMed, ACS Omega)
    Finally, concomitant with cell cycle arrest, the underlying molecular mechanisms of Mtx-C in AML cells include myeloid differentiation, as evidenced by the increased expression of PU.1, myeloperoxidase, CD15, CD11b, and CD14 in the AML and LSC populations with the participation of p38 mitogen-activated protein kinase. Thus, we showed that Mtx-C simultaneously induced cell cycle arrest and myeloid differentiation in AML lineages and in the LSC population, providing insights into new therapeutic alternatives for the treatment of AML based on naturally occurring molecules.
    Journal
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    CHEK1 (Checkpoint kinase 1) • CD14 (CD14 Molecule) • ITGAM (Integrin, alpha M) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • CCNB1 (Cyclin B1) • MPO (Myeloperoxidase)
    2ms
    An update on small molecule compounds targeting synthetic lethality for cancer therapy. (PubMed, Eur J Med Chem)
    This article illuminated recent progress in the field of medicinal chemistry centered on the rational design of agents capable of eliciting SL specifically in neoplastic cells. It is envisioned that innovative strategies harnessing SL for small molecule design may unlock novel prospects for targeted cancer therapeutics going forward.
    Review • Journal • Synthetic lethality
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    CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • RAD51 (RAD51 Homolog A) • CHEK1 (Checkpoint kinase 1) • RAD52 (RAD52 Homolog DNA Repair Protein)
    2ms
    Combined inhibition of RAD51 and CHK1 causes synergistic toxicity in cisplatin resistant cancer cells by triggering replication fork collapse. (PubMed, Int J Cancer)
    Synergistic cytolethal effects were achieved after combined treatment with low to moderate doses of the non-genotoxic RAD51-inhibitor (RAD51i) B02 and CHK1-inhibitor (CHK1i) PF477736. Based on these data, we suggest combined inhibition of RAD51 and CHK1 to overcome acquired cisplatin resistance of malignant cells. We propose that the molecular mechanism of this synergistic toxicity relies on a simultaneous inactivation of two key DNA damage tolerance pathways regulating replication fork restart, thereby circumventing the activation of alternative compensatory mechanisms and, in consequence, eventually effectively triggering apoptotic cell death by replication fork collapse.
    Journal
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    RAD51 (RAD51 Homolog A) • CHEK1 (Checkpoint kinase 1)
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    cisplatin • PF-00477736
    2ms
    Circulating Tumor DNA (ctDNA) Monitoring in the Assessment and Prediction of the Efficacy of PARP Inhibitors (PARPi) (clinicaltrials.gov)
    P=N/A, N=30, Recruiting, Sun Yat-sen University | Trial completion date: Aug 2023 --> Aug 2025
    Trial completion date • Circulating tumor DNA
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    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • FANCL (FA Complementation Group L) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha)
    |
    BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • CHEK1 mutation • RAD54L mutation • BRCA1 mutation + ATM mutation • CHEK1 expression
    3ms
    Cigarette smoke extract induces malignant transformation and DNA damage via c-MET phosphorylation in human bronchial epithelial cells. (PubMed, Ecotoxicol Environ Saf)
    The addition of PHA665752, a specific inhibitor of c-MET, or knock-down with c-MET both attenuated DNA damage, while overexpression of c-MET exacerbated DNA damage. Thus, c-MET phosphorylation may be involved in CSE-induced DNA damage, providing a potential target for intervention in the prevention and treatment of smoking-induced lung diseases.
    Journal
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    CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)
    |
    PHA665752
    3ms
    Correlation between Molecular Docking and the Stabilizing Interaction of HOMO-LUMO: Spirostans in CHK1 and CHK2, an In Silico Cancer Approach. (PubMed, Int J Mol Sci)
    In addition, Highest Occupied Molecular Orbital-Lowest Unoccupied Molecular Orbital (HOMO-LUMO) interactions were analyzed to study the stability of interactions between the selected enzymes and spirostans resulting in the predominant gaps from HOMOCHKs to LUMOSp (Highest Occupied Molecular Orbital of CHKs-Lowest Unoccupied Molecular Orbital of spirostan). In brief, this study presents the selection inhibitors of CHK1 and CHK2 as a potential treatment for cancer using a combination of molecular docking and dynamics, ADMETx predictons, and HOMO-LUMO calculation for selection.
    Journal
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    CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)
    3ms
    DNA-Damaging Therapies in Patients With Prostate Cancer and Pathogenic Alterations in Homologous Recombination Repair Genes. (PubMed, JCO Precis Oncol)
    Patients with BRCA1/2-mutated PC had significantly improved outcomes to PARPi but not platinum chemotherapy compared with those with HRR mutations without direct BRCA complex interaction.
    Retrospective data • Journal • BRCA Biomarker • PARP Biomarker
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    HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • RAD51B (RAD51 Paralog B) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • FANCL (FA Complementation Group L) • GEN1 (GEN1 Holliday junction 5' flap endonuclease) • RAD54L2 (RAD54 Like 2)
    3ms
    NCI-2017-02296: Testing Olaparib in Patients With Advanced or Metastatic (Cancer That Has Spread) Bladder Cancer and Other Genitourinary Tumors With DNA-Repair Genetic Changes (clinicaltrials.gov)
    P2; Trial completion date: Aug 2024 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Dec 2025
    Trial completion date • Trial primary completion date • Tumor mutational burden • Metastases
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    TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • ABL1 (ABL proto-oncogene 1) • MSI (Microsatellite instability) • STK11 (Serine/threonine kinase 11) • NPM1 (Nucleophosmin 1) • POLE (DNA Polymerase Epsilon) • CCND1 (Cyclin D1) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • ATRX (ATRX Chromatin Remodeler) • CHEK2 (Checkpoint kinase 2) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • RAD51 (RAD51 Homolog A) • POLD1 (DNA Polymerase Delta 1) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • FANCL (FA Complementation Group L) • BRD4 (Bromodomain Containing 4) • DOT1L (DOT1 Like Histone Lysine Methyltransferase) • FANCE (FA Complementation Group E) • FANCG (FA Complementation Group G) • IKBKE (Inhibitor Of Nuclear Factor Kappa B Kinase Subunit Epsilon) • FANCC (FA Complementation Group C)
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    FoundationOne® CDx • FoundationOne® Liquid CDx
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    Lynparza (olaparib)
    3ms
    Microcystin-LR activates serine/threonine kinases and alters the phosphoproteome in human HepaRG cells. (PubMed, Toxicon)
    Many of the kinases and pathways described above play crucial roles in the development of HCC by affecting processes such as invasion and metastasis. Overall, our data indicate that MCLR-mediated changes in protein phosphorylation involve biological pathways related to carcinogenesis that may contribute to the development of HCC.
    Journal
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    KDR (Kinase insert domain receptor) • CHEK1 (Checkpoint kinase 1) • AURKB (Aurora Kinase B)
    3ms
    ATR/Chk1 interacting lncRNA modulates DNA damage response to induce breast cancer chemoresistance. (PubMed, Cell Insight)
    ACIL protects cancer cells against DNA damages by inducing cell cycle arrest, stabilizing replication forks and inhibiting unscheduled origin firing, thereby guarding against replication catastrophe and contributing to DNA damage repair. These findings demonstrate a lncRNA-dependent mechanism of activating the ATR-Chk1 pathway and highlight the potential of utilizing ACIL as a predictive biomarker for chemotherapy sensitivity, as well as targeting ACIL to reverse chemoresistance in breast cancer.
    Journal
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    CHEK1 (Checkpoint kinase 1)
    3ms
    Activity-based protein profiling and global proteome analysis reveal MASTL as a potential therapeutic target in gastric cancer. (PubMed, Cell Commun Signal)
    Our multi-proteomic analyses suggest that targeting MASTL could be a promising therapy for advanced gastric cancer, potentially through the reduction of tumor-promoting proteins including NEDD4-1. This study enhances our understanding of kinase signaling pathways in GC and provides new insights for potential treatment strategies.
    Journal
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    STK11 (Serine/threonine kinase 11) • CHEK1 (Checkpoint kinase 1) • NEDD4 (NEDD4 E3 Ubiquitin Protein Ligase)
    3ms
    Oleandrin enhances radiotherapy sensitivity in lung cancer by inhibiting the ATM/ATR-mediated DNA damage response. (PubMed, Phytother Res)
    The combined treatment of Oleandrin and radiotherapy demonstrated superior inhibition of tumor proliferation compared to either treatment alone. Our findings highlight Oleandrin as a novel and effective inhibitor of ATM and ATR kinase, offering new possibilities for the development of clinical radiosensitizing adjuvants.
    Journal
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    CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)
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    oleandrin (PBI-05204)
    3ms
    Ocoxin Oral Solution Triggers DNA Damage and Cell Death in Ovarian Cancer. (PubMed, Nutrients)
    Moreover, such reduction in tumor proliferation was caused by the induction of DNA damage as corroborated by the in vivo phosphorylation of CHK2 and Histone H2AX. Finally, OOS potentiated the action of carboplatin or olaparib, the standard of care treatments used in ovarian clinics, opening the possibility of including OOS in combination with those standard of care agents in patients with ovarian cancer.
    Journal
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    CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)
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    Lynparza (olaparib) • carboplatin
    3ms
    SLFN11 and ATR as targets for overcoming cisplatin resistance in ovarian cancer cells. (PubMed, Biochim Biophys Acta Mol Basis Dis)
    HDAC inhibition using entinostat returned an epigenetic downregulation of SLFN11 in W1CR cells, caused SLFN11 re-expression and re-sensitized these cells to cisplatin...In contrast, inhibition of the DNA damage repair master regulator ATR using sub-toxic concentrations of elimusertib sensitized parental cell lines as well as intrinsically resistant EFO21 cells to cisplatin, and fully reversed acquired cisplatin resistance in cisplatin-adapted sublines W1CR, A2780cis, and KuramochirCDDP2000...In conclusion, SLFN11 and ATR are involved in ovarian cancer cisplatin resistance. Although our data identify ATR as key target for tackling cisplatin resistance in ovarian cancer, future studies are needed to identify biomarkers that indicate, which individual ovarian cancers benefit from SLFN11 re-activation and/or ATR inhibition.
    Journal
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    SLFN11 (Schlafen Family Member 11) • CHEK1 (Checkpoint kinase 1)
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    cisplatin • elimusertib (BAY 1895344) • Jingzhuda (entinostat)