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GENE:

CHEK1 (Checkpoint kinase 1)

News alerts, weekly reports and conference planners

Combining germline, tissue and liquid biopsy analysis by comprehensive genomic profiling to improve the yield of actionable variants in a real-world cancer cohort. (PubMed, J Transl Med)

Our study confirms the clinical relevance of performing extended parallel tumor DNA and cfDNA testing to broaden therapeutic options, to longitudinally monitor cfDNA during patient treatment, and to uncover possible hereditary predisposition following tumor sequencing in patient care.

3 days ago

Journal • Real-world evidence • Liquid biopsy • BRCA Biomarker • Real-world • Biopsy

BRCA1 (Breast cancer 1, early onset) • ATM (ATM serine/threonine kinase) • CHEK1 (Checkpoint kinase 1)

BRAF V600E • BRAF V600

TruSight Oncology 500 Assay

Melatonin ameliorates 10-hydroxycamptothecin-induced oxidative stress and apoptosis via autophagy-regulated p62/Keap1/Nrf2 pathway in mouse testicular cells. (PubMed, J Pineal Res)

Mechanistically, melatonin-activated autophagy proteins (ATG7, Beclin1, and LC3bII/I) may induce p62-dependent autophagy to degrade Keap1, eliciting Nrf2 from Keap1-Nrf2 interaction to promote antioxidant enzyme expression such as HO-1, which would salvage HCPT-induced ROS production and mitochondrial dysfunction. Collectively, this study reveals that melatonin therapy may protect testicular cells from HCPT-induced damage via the activation of autophagy, which alleviates oxidative stress, mitochondrial dysfunction, and cell apoptosis.

6 days ago

Preclinical • Journal • IO biomarker

BCL2 (B-cell CLL/lymphoma 2) • KEAP1 (Kelch Like ECH Associated Protein 1) • CHEK1 (Checkpoint kinase 1) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • ATG7 (Autophagy Related 7) • BECN1 (Beclin 1)

10d

Nobiletin Inhibits Breast Cancer Stem Cell by Regulating the Cell Cycle: A Comprehensive Bioinformatics Analysis and In Vitro Experiments. (PubMed, Nutr Cancer)

NOB decreased G0/G1, but increased the G2/M cell population. These findings showed that NOB is a potential therapeutic candidate for BCSCs treatment by regulating cell cycle.

10 days ago

Preclinical • Journal • Cancer stem • BRCA Biomarker

BRCA1 (Breast cancer 1, early onset) • TOP2A (DNA topoisomerase 2-alpha) • CHEK1 (Checkpoint kinase 1) • UCHL5 (Ubiquitin C-Terminal Hydrolase L5)

11d

Clinical actionability of BRCA2 alterations in uterine leiomyosarcoma: a molecular tumor board case report and a cBioPortal comprehensive analysis. (PubMed, Oncologist)

uLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations.

11 days ago

Journal • BRCA Biomarker • PARP Biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PALB2 (Partner and localizer of BRCA2) • 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) • FANCL (FA Complementation Group L) • FANCI (FA Complementation Group I) • FANCM (FA Complementation Group M) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCG (FA Complementation Group G) • FANCB (FA Complementation Group B) • FANCC (FA Complementation Group C)

BRCA2 mutation

Zejula (niraparib)

12d

Target prediction and potential application of dihydroartemisinin on hepatocarcinoma treatment. (PubMed, Naunyn Schmiedebergs Arch Pharmacol)

Molecular docking suggests that all hub genes form a stable interaction with DHA for optimal binding energy were all less than - 5 kcal/mol. Dihydroartemisinin might be a potent and safe anticarcinogen based on its biological safety and effective therapeutic effect.

12 days ago

Journal

TOP2A (DNA topoisomerase 2-alpha) • TYMS (Thymidylate Synthetase) • AURKA (Aurora kinase A) • CHEK1 (Checkpoint kinase 1) • CCNA2 (Cyclin A2) • CCNB2 (Cyclin B2) • CDK1 (Cyclin-dependent kinase 1) • KIF11 (Kinesin Family Member 11) • CCNB1 (Cyclin B1)

20d

Validation of Core Ingredients and Molecular Mechanism of Cinobufotalin Injection Against Liver Cancer. (PubMed, Drug Des Devel Ther)

Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay. Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs.

20 days ago

Journal

CCNE1 (Cyclin E1) • CDK4 (Cyclin-dependent kinase 4) • PLK1 (Polo Like Kinase 1) • CHEK1 (Checkpoint kinase 1) • CDK1 (Cyclin-dependent kinase 1) • CCNB1 (Cyclin B1)

21d

DNA Checkpoint Gene Mutation as a Biomarker for Immune Checkpoint Inhibitor Therapy in Advanced Biliary Tract Cancer. (PubMed, Anticancer Res)

The DNACHK pathway is expected to serve as a potential biomarker for ICI treatment.

21 days ago

Journal • Checkpoint inhibition • BRCA Biomarker • IO biomarker • Metastases

TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • ATM (ATM serine/threonine kinase) • CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1) • TP53BP1 (Tumor Protein P53 Binding Protein 1)

ATM mutation

21d

Antitumoral Activity of the Universal Methyl Donor S-Adenosylmethionine in Glioblastoma Cells. (PubMed, Molecules)

Finally, AdoMet inhibited DNA repair and induced cell cycle arrest, apoptosis, and mitotic catastrophe in patient-derived GBM cells. In light of these results, AdoMet could be considered a potential adjuvant in GBM therapy.

21 days ago

Journal • BRCA Biomarker

BRCA1 (Breast cancer 1, early onset) • RAD51 (RAD51 Homolog A) • CHEK1 (Checkpoint kinase 1)

22d

Novel Amidine Derivative K1586 Sensitizes Colorectal Cancer Cells to Ionizing Radiation by Inducing Chk1 Instability. (PubMed, Int J Mol Sci)

Exposure to K1586 enhanced the degradation of Chk1 in a time- and dose-dependent manner, increasing replication stress and sensitizing colorectal cancer cells to radiation. Taken together, the results suggest that a novel amidine derivative may have potential as a radiotherapy-sensitization agent that targets Chk1.

22 days ago

Journal

CHEK1 (Checkpoint kinase 1)

22d

Irradiated Tumour Cell-Derived Microparticles Upregulate MHC-I Expression in Cancer Cells via DNA Double-Strand Break Repair Pathway. (PubMed, Cancer Lett)

Furthermore, phosphorylation of STAT1/3 following the activation of ATM/ATR/CHK1 is indispensable for the DSB-dependent upregulation of MHC-I. Therefore, our findings reveal the role of RT-MP-induced DSBs and the subsequent DNA repair signalling pathway in MHC-I expression and provide mechanistic insights into the regulation of MHC-I expression after DSBs.

22 days ago

Journal • Tumor cell

CHEK1 (Checkpoint kinase 1)

ATM expression

22d

The KRAS, ATR and CHEK1 expression levels in endometrial cancer are the risk factors predicting recurrence. (PubMed, PLoS One)

Our findings indicate that markers of replicative stress may play a significant role in ECE pathogenesis. Determining their levels in tumor samples after primary treatment could help define patients at high risk of recurrence and guide consequent courses of treatment.

22 days ago

Journal

KRAS (KRAS proto-oncogene GTPase) • CHEK1 (Checkpoint kinase 1)

KRAS expression

24d

PARP1 UFMylation ensures the stability of stalled replication forks. (PubMed, Proc Natl Acad Sci U S A)

Finally, we observed that PARP1 UFMylation-deficient knock-in mice exhibited increased sensitivity to replication stress caused by anticancer treatments. Thus, we demonstrate that PARP1 UFMylation promotes CHK1 activation and replication fork stability during replication stress, thus safeguarding genome integrity.

24 days ago

Journal • PARP Biomarker

PARP1 (Poly(ADP-Ribose) Polymerase 1) • CHEK1 (Checkpoint kinase 1)

27d

Mechanism of Musashi2 affecting radiosensitivity of lung cancer by modulating DNA damage repair. (PubMed, MedComm (2020))

Furthermore, we revealed the potential mechanism of MSI2 recruitment into the nucleus with the assistance of RBM17 to activate ATR to promote radioresistance. This study provides novel insights into the potential application of MSI2 as a new target in lung cancer radiotherapy.

27 days ago

Journal

CHEK1 (Checkpoint kinase 1) • MSI2 (Musashi RNA Binding Protein 2) • RBM17 (RNA Binding Motif Protein 17)

Network pharmacology and molecular docking reveal the mechanisms of curcumin activity against esophageal squamous cell carcinoma. (PubMed, Front Pharmacol)

The Transwell invasion results validated that CUR can significantly inhibit the invasion rates of ESCC cells. Collectively, these findings indicate that CUR exhibits pharmacological effects on multiple targets and pathways in ESCC.

1 month ago

Journal

CDK6 (Cyclin-dependent kinase 6) • CHEK1 (Checkpoint kinase 1) • IL17A (Interleukin 17A)

Cabozantinib and Pamiparib for the Treatment of Advanced of Refractory Solid Tumors (clinicaltrials.gov)

P1, N=44, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting

1 month ago

Enrollment open • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • ARID1A (AT-rich interaction domain 1A) • CHEK2 (Checkpoint kinase 2) • RAD50 (RAD50 Double Strand Break Repair Protein) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • CHEK1 (Checkpoint kinase 1) • EMSY (EMSY Transcriptional Repressor BRCA2 Interacting)

BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CHEK2 mutation • RAD50 mutation • CHEK1 mutation • CHEK1 expression

Cabometyx (cabozantinib tablet) • Partruvix (pamiparib)

Enhanced Therapeutic Efficacy of the Nanoscale Fluoropyrimidine Polymer CF10 in a Rat Colorectal Cancer Liver Metastasis Model. (PubMed, Cancers (Basel))

Combination chemotherapy regimens that include fluoropyrimidine (FP) drugs, e.g., 5-fluorouracil (5-FU), are central to the treatment of colorectal cancer liver metastases (CRLMs), a major cause of cancer mortality...Importantly, CF10 was significantly more effective than 5-FU at inhibiting tumor progression (~90% reduction) in the CC531/WAG/Rij CRLM model. Our results reveal strong potential for CF10 to be used for CRLM treatment.

1 month ago

Preclinical • Journal

CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)

5-fluorouracil

Development of gemcitabine-modified miRNA mimics as cancer therapeutics for pancreatic ductal adenocarcinoma. (PubMed, Mol Ther Oncol)

Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth in vivo without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of Gem-modified miRNAs as a treatment strategy for PDAC.

1 month ago

Journal

YAP1 (Yes associated protein 1) • CHEK1 (Checkpoint kinase 1) • FOXA1 (Forkhead Box A1) • BMI1 (BMI1 proto-oncogene, polycomb ring finger) • MIR15A (MicroRNA 15a) • MIR194 (MicroRNA 194)

gemcitabine

The luciferase-based in vivo protein-protein interaction assay revealed that CHK1 promotes PP2A and PME-1 interaction. (PubMed, J Biol Chem)

On the contrary, in vitro phosphatase assay showed that CHK1 is the substrate of PP2A, and PME-1 hindered PP2A-mediated dephosphorylation of CHK1. Our data provides novel insights into the molecular mechanisms governing the PME-1/PP2Ac PPI and the triad relationship between PP2A, PME-1, and CHK1.

1 month ago

Preclinical • Journal

CHEK1 (Checkpoint kinase 1) • PPP2CA (Protein Phosphatase 2 Catalytic Subunit Alpha 2)

Construction and validation of a hypoxia-related gene signature to predict the prognosis of breast cancer. (PubMed, BMC Cancer)

Based on 9 DEHRGs, a reliable signature was established through the bioinformatic method. It could accurately predict the prognosis of breast cancer patients. Cell line experiment indicated that PSME2 played a protective role. Summarily, we provided a new insight to predict the prognosis of breast cancer by hypoxia-related genes.

1 month ago

Journal • Tumor mutational burden • Gene Signature

TMB (Tumor Mutational Burden) • CHEK1 (Checkpoint kinase 1) • CA9 (Carbonic anhydrase 9) • CD24 (CD24 Molecule) • HOTAIR (HOX Transcript Antisense RNA) • FOXM1 (Forkhead Box M1) • ALOX15B (Arachidonate 15-Lipoxygenase Type B)

BrUOG 360: A Study of Copanlisib Combined With Rucaparib in Patients With Metastatic Castration-resistant Prostate Cancer (clinicaltrials.gov)

P1/2, N=13, Active, not recruiting, Brown University | Trial completion date: May 2024 --> Jan 2027 | Trial primary completion date: Jan 2024 --> Jan 2027

1 month ago

Trial completion date • Trial primary completion date • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • FANCA (FA Complementation Group A) • 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)

BRIP1 mutation

Rubraca (rucaparib) • Aliqopa (copanlisib)

2ms

Ataxia telangiectasia and Rad3-related (ATR) inhibition by VE-822 potently reversed 5-flourouracil resistance in colorectal cancer cells through targeting DNA damage response. (PubMed, Mol Biol Rep)

The simultaneous treatment of resistant colorectal cancer cells with 5-FU and ATR inhibitor, VE-822, was demonstrated to be effective in reversing drug resistance and potentiating 5-FU mediated anticancer effects via targeting DNA damage.

2 months ago

Journal

ABCC1 (ATP Binding Cassette Subfamily C Member 1) • CHEK1 (Checkpoint kinase 1) • H2AX (H2A.X Variant Histone)

5-fluorouracil • berzosertib (M6620)

2ms

Triple-Negative Breast Cancer and Emerging Therapeutic Strategies: ATR and CHK1/2 as Promising Targets. (PubMed, Cancers (Basel))

In this article, we introduce ATR and CHK1/2 inhibitors as promising therapeutic approaches for the management of TNBC. Preclinical and clinical studies performed evaluating ATR and CHK1/2 inhibitors for the treatment of TNBC and associated challenges encountered in this context to date are reviewed.

2 months ago

Review • Journal

CHEK1 (Checkpoint kinase 1)

2ms

Cell Context is the third axis of synergy for the combination of ATR inhibition and cisplatin in Ewing sarcoma. (PubMed, Clin Cancer Res)

These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule.

2 months ago

Journal

EWSR1 (EWS RNA Binding Protein 1) • CHEK1 (Checkpoint kinase 1) • FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor)

cisplatin • berzosertib (M6620) • M9831

2ms

Clinical translation for targeting DNA damage repair in non-small cell lung cancer: a review. (PubMed, Transl Lung Cancer Res)

Additionally, promising new compounds targeting DDR, such as ATR, CHK1, CHK2, DNA-PK, and WEE1, had demonstrated great potential for tumor selectivity. In this review, we provide an overview of DDR pathways and discuss the clinical translation of DDR inhibitors in NSCLC, including their application as single agents or in combination with chemotherapy, radiotherapy, and immunotherapy.

2 months ago

Review • Journal • PARP Biomarker • IO biomarker

CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)

2ms

ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells. (PubMed, Oncotarget)

Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1) • CASP3 (Caspase 3) • ANXA5 (Annexin A5) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)

Venclexta (venetoclax) • cladribine • fludarabine IV • thiotepa • busulfan

2ms

ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway. (PubMed, Nat Commun)

We find that ZNF827 accumulates at stalled forks and DNA damage sites, where it activates ATR and promotes the engagement of homologous recombination-mediated DNA repair. Additionally, we demonstrate that ZNF827 depletion inhibits replication initiation and sensitizes cancer cells to the topoisomerase inhibitor topotecan, revealing ZNF827 as a therapeutic target within the DNA damage response pathway.

2 months ago

Journal

CHEK1 (Checkpoint kinase 1) • RPA1 (Replication Protein A1)

topotecan

2ms

SYNERGY-AI: Artificial Intelligence Based Precision Oncology Clinical Trial Matching and Registry (clinicaltrials.gov)

P=N/A, N=50000, Recruiting, Massive Bio, Inc. | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Dec 2026

2 months ago

Trial completion date • Trial primary completion date

EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ER (Estrogen receptor) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • FGFR2 (Fibroblast growth factor receptor 2) • PTEN (Phosphatase and tensin homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • BCL2 (B-cell CLL/lymphoma 2) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • STK11 (Serine/threonine kinase 11) • NPM1 (Nucleophosmin 1) • HRAS (Harvey rat sarcoma viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • RB1 (RB Transcriptional Corepressor 1) • CLDN18 (Claudin 18) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • JAK2 (Janus kinase 2) • NRG1 (Neuregulin 1) • POLE (DNA Polymerase Epsilon) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • PD-1 (Programmed cell death 1) • CCND1 (Cyclin D1) • MCL1 (Myeloid cell leukemia 1) • KDR (Kinase insert domain receptor) • PBRM1 (Polybromo 1) • BAP1 (BRCA1 Associated Protein 1) • VEGFA (Vascular endothelial growth factor A) • BCL6 (B-cell CLL/lymphoma 6) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • PTCH1 (Patched 1) • FGFR4 (Fibroblast growth factor receptor 4) • MSH6 (MutS homolog 6) • CDK4 (Cyclin-dependent kinase 4) • MSH2 (MutS Homolog 2) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • WT1 (WT1 Transcription Factor) • ATRX (ATRX Chromatin Remodeler) • BRCA (Breast cancer early onset) • RAF1 (Raf-1 Proto-Oncogene Serine/Threonine Kinase) • TSC2 (TSC complex subunit 2) • CHEK2 (Checkpoint kinase 2) • PD-L2 (Programmed Cell Death 1 Ligand 2) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • JAK1 (Janus Kinase 1) • FANCA (FA Complementation Group A) • TSC1 (TSC complex subunit 1) • MDM4 (The mouse double minute 4) • POLD1 (DNA Polymerase Delta 1) • CDK6 (Cyclin-dependent kinase 6) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • AURKA (Aurora kinase A) • JAK3 (Janus Kinase 3) • RICTOR (RPTOR Independent Companion Of MTOR Complex 2) • CHEK1 (Checkpoint kinase 1) • GATA6 (GATA Binding Protein 6) • MSH3 (MutS Homolog 3) • TGFBR2 (Transforming Growth Factor Beta Receptor 2) • GNAS (GNAS Complex Locus) • MYCL (MYCL Proto-Oncogene BHLH Transcription Factor) • AKT2 (V-akt murine thymoma viral oncogene homolog 2) • CCND2 (Cyclin D2) • CCND3 (Cyclin D3) • CSF1R (Colony stimulating factor 1 receptor) • MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1) • ERCC4 (ERCC Excision Repair 4, Endonuclease Catalytic Subunit) • HDAC1 (Histone Deacetylase 1) • PRDM1 (PR/SET Domain 1) • ZNF217 (Zinc Finger Protein 217) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • GATA3 (GATA binding protein 3) • PARP2 (Poly(ADP-Ribose) Polymerase 2) • PARP3 (Poly(ADP-Ribose) Polymerase Family Member 3) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A) • ACVR1B (Activin A Receptor Type 1B) • ZNF703 (Zinc Finger Protein 703)

HER-2 mutation • BAP1 mutation • AKT1 mutation • FGFR3 fusion • JAK3 mutation

2ms

ROAR: Rucaparib in Nonmetastatic prOstAte With BRCAness (clinicaltrials.gov)

P2, N=7, Terminated, University of Utah | Active, not recruiting --> Terminated; New standard of care for study participant population

2 months ago

Trial termination • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • 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) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin))

Rubraca (rucaparib)

2ms

The novel ATR inhibitor M1774 induces replication protein overexpression and broad synergy with DNA-targeted anticancer drugs. (PubMed, Mol Cancer Ther)

As single agent, M1774 suppressed cancer cell viability at nanomolar concentrations, showing greater activity than ceralasertib and berzosertib, but less potency than gartisertib and elimusertib in the small-cell lung cancer H146, H82, and DMS114 cell lines. Low dose of M1774 was found highly synergistic with a broad spectrum of clinical DDAs including TOP1 inhibitors (SN-38/irinotecan, topotecan, exatecan, and exatecan), the TOP2 inhibitor etoposide, cisplatin, the RNA polymerase II inhibitor lurbinectedin, and the PARP inhibitor talazoparib in various models including cancer cell lines, patient-derived organoids, and mouse xenograft models. Furthermore, we demonstrate that M1774 reverses chemoresistance to anticancer DDAs in cancer cells lacking SLFN11 expression, suggesting that SLFN11 can be utilized for patient selection in upcoming clinical trials.

2 months ago

Journal • PARP Biomarker

SLFN11 (Schlafen Family Member 11) • PLK1 (Polo Like Kinase 1) • CHEK1 (Checkpoint kinase 1) • CCNB1 (Cyclin B1) • CDC45 (Cell Division Cycle 45)

SLFN11 expression

cisplatin • Talzenna (talazoparib) • etoposide IV • irinotecan • berzosertib (M6620) • ceralasertib (AZD6738) • topotecan • elimusertib (BAY 1895344) • Zepzelca (lurbinectedin) • tuvusertib (M1774) • gartisertib (M4344)

2ms

DNA damage response defects in hematologic malignancies: mechanistic insights and therapeutic strategies. (PubMed, Blood)

The nature of the DDR-immune interface and the cellular vulnerabilities conferred by DDR defects may nonetheless be disease-specific and remain incompletely understood in many hematologic malignancies. Their comprehensive elucidation will be critical for optimizing therapeutic strategies to target DDR defects in these diseases.

2 months ago

Journal • BRCA Biomarker

CHEK1 (Checkpoint kinase 1)

2ms

Inhibition of Chk1 stimulates cytotoxic action of platinum-based drugs and TRAIL combination in human prostate cancer cells. (PubMed, Biol Chem)

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.

2 months ago

Journal

CHEK1 (Checkpoint kinase 1)

cisplatin • MK-8776

3ms

ORCHID: Study of Olaparib in Metastatic Renal Cell Carcinoma Patients With DNA Repair Gene Mutations (clinicaltrials.gov)

P2, N=20, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Mar 2025 --> Mar 2026 | Trial primary completion date: Mar 2024 --> Mar 2025

3 months ago

Trial completion date • Trial primary completion date • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BAP1 (BRCA1 Associated Protein 1) • 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)

BRCA1 mutation • ATM mutation • PALB2 mutation • CDK12 mutation • CHEK2 mutation • BRIP1 mutation • RAD51C mutation • RAD51D mutation • RAD51B mutation • BARD1 mutation • CHEK1 mutation • RAD54L mutation • RAD51 mutation • CHEK1 expression

Lynparza (olaparib)

3ms

Carboplatin in metastatic castration-resistant prostate cancer patients with molecular alterations of the DNA damage repair pathway: the PRO-CARBO phase II trial. (PubMed, Ther Adv Urol)

Larger experience is needed in mCRPC with BRCA alterations. NCT03652493, EudraCT ID number 2017-004764-35.

3 months ago

P2 data • Journal • BRCA Biomarker • PARP Biomarker • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)

BRCA2 mutation

carboplatin

3ms

The ATR inhibition by Elimusertib enhances the radiosensitivity of MDA-MB-231 triple negative breast cancer in vitro. (PubMed, Int J Radiat Biol)

ATR inhibition by Elimusertib in combination with RT may be a promising new treatment strategy in the treatment of TNBC. However, further experiments should be performed to elucidate the underlying molecular mechanisms of the therapeutic efficacy of this combination treatment and its association with DNS repair mechanisms in TNBC, in vitro and in vivo.

3 months ago

Preclinical • Journal

CHEK1 (Checkpoint kinase 1) • ANXA5 (Annexin A5)

elimusertib (BAY 1895344)

3ms

Cucurbitacin B suppresses hepatocellular carcinoma progression through inducing DNA damage-dependent cell cycle arrest. (PubMed, Phytomedicine)

This study demonstrated for the first time that CuB could effectively impede HCC progression by inducing DNA damage-dependent cell cycle arrest without directly triggering cell death, such as necrosis and apoptosis. The effect was achieved through ataxia telangiectasia mutated (ATM)-dependent p53-p21-CDK1 and checkpoint kinase 1 (CHK1)-CDC25C signaling pathways. These findings indicate that CuB may be used as an anti-HCC drug, when the current findings are confirmed by independent studies and after many more clinical phase 1, 2, 3, and 4 testings have been done.

3 months ago

Journal

CHEK1 (Checkpoint kinase 1) • IGF2BP1 (Insulin Like Growth Factor 2 MRNA Binding Protein 1) • PCNA (Proliferating cell nuclear antigen) • CDC25C (Cell Division Cycle 25C) • CDK1 (Cyclin-dependent kinase 1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1)

TP53 mutation

3ms

A novel HDAC6 inhibitor interferes microtubule dynamics and spindle assembly checkpoint and sensitizes cisplatin-induced apoptosis in castration-resistant prostate cancer. (PubMed, Prostate)

The data suggest that 25202 is a novel selective and potent HDAC6 inhibitor. Compound 25202 blocks HDAC6 activity and interferes microtubule dynamics, leading to SAC activation and mitotic arrest prolongation that eventually cause apoptosis of CRPC cells. Furthermore, 25202 sensitizes cisplatin-induced cell apoptosis through impeding DNA damage repair pathways.

3 months ago

Journal • IO biomarker

BCL2 (B-cell CLL/lymphoma 2) • CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1) • HDAC6 (Histone Deacetylase 6) • CDC20 (Cell Division Cycle 20) • CDK1 (Cyclin-dependent kinase 1) • BUB1 (BUB1 Mitotic Checkpoint Serine/Threonine Kinase) • BUB1B (BUB1 Mitotic Checkpoint Serine/Threonine Kinase B) • CCNB1 (Cyclin B1)

HDAC6 expression

cisplatin • docetaxel

3ms

Pembrolizumab, Olaparib, and Temozolomide for People With Glioma (clinicaltrials.gov)

P2, N=57, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

3 months ago

Trial completion date • Trial primary completion date

EGFR (Epidermal growth factor receptor) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • FGFR (Fibroblast Growth Factor Receptor) • CDK12 (Cyclin dependent kinase 12) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • 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)

CDKN2A deletion • BRIP1 mutation • RAD51C mutation • RAD51B mutation • BARD1 mutation • IDH wild-type

Keytruda (pembrolizumab) • Lynparza (olaparib) • temozolomide

3ms

Niraparib Plus Carboplatin in Patients With Homologous Recombination Deficient Advanced Solid Tumor Malignancies (clinicaltrials.gov)

P1, N=23, Terminated, Georgetown University | Trial completion date: Jul 2025 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2025 --> Oct 2023; Lack of accrual

3 months ago

Trial completion date • Trial termination • Trial primary completion date • Metastases

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • ARID1A (AT-rich interaction domain 1A) • BAP1 (BRCA1 Associated Protein 1) • KMT2D (Lysine Methyltransferase 2D) • 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) • MLL2 (Myeloid/lymphoid or mixed-lineage leukemia 2) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • WRN (WRN RecQ Like Helicase) • FANCG (FA Complementation Group G) • ABRAXAS1 (Abraxas 1 BRCA1 A Complex Subunit 2) • SLX4 (SLX4 Structure-Specific Endonuclease Subunit)

BARD1 mutation • WRN mutation

carboplatin • Zejula (niraparib)

3ms

Photoactivation Inducing Multifunctional Coupling of Fluorophore for Efficient Tumor Therapy in Situ. (PubMed, Adv Mater)

Thus, the combination of cell cycle block inducing apoptosis, PDT (photodynamic therapy) and PTT (photothermal therapy) treatment significantly suppressed solid tumor in vivo antitumor efficacy explorations. This is a novel finding in developing photoactivatable molecules, as well as the broad applicability of photoimaging and phototherapy in tumor-related areas.

3 months ago

Journal

CHEK1 (Checkpoint kinase 1)

3ms

Cabozantinib and Pamiparib for the Treatment of Advanced of Refractory Solid Tumors (clinicaltrials.gov)

P1, N=44, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

3 months ago

Enrollment closed

BRCA2 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • CHEK2 mutation • RAD50 mutation • CHEK1 mutation • CHEK1 expression

Cabometyx (cabozantinib tablet) • Partruvix (pamiparib)

3ms

CKS1B as a potential target for prognostic assessment and intervention in pancreatic cancer and its role in abnormal proliferation and cellular phenotype through mediation of cell cycle signaling pathways. (PubMed, Saudi Med J)

The CKS1B may serve as a novel potential prognostic factor in pancreatic cancer and is involved in the abnormal proliferation biology phenotype by mediating cell cycle signaling pathways.

3 months ago

Journal

CHEK1 (Checkpoint kinase 1) • PKMYT1 (Protein Kinase Membrane Associated Tyrosine/Threonine 1) • RASGRF1 (Ras Protein Specific Guanine Nucleotide Releasing Factor 1) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1)

3ms

Natural pentacyclic triterpenoid from Pristimerin sensitizes p53-deficient tumor to PARP inhibitor by ubiquitination of Chk1. (PubMed, Pharmacol Res)

Taken together, inhibition of Chk1 by pristimerin has been observed to induce DNA repair deficiency, which may expand the application of olaparib in BRCA-proficient cancers harboring TP53 mutations. Thus, pristimerin can be combined for PARP inhibitor-based therapy.

3 months ago

Journal • BRCA Biomarker • PARP Biomarker

TP53 (Tumor protein P53) • BRCA (Breast cancer early onset) • CHEK1 (Checkpoint kinase 1) • DRD (DNA Repair Deficiency)

TP53 mutation • DDR • TP53 expression • BRCA mutation • DRD

Lynparza (olaparib)