adavosertib (AZD1775) / AstraZeneca, Merck (MSD) - LARVOL DELTA

Prostate Cancer Biomarker Enrichment and Treatment Selection (clinicaltrials.gov) - P2 | N=200 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial primary completion date: Jun 2025 ➔ Oct 2024

Biomarker • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Combined inhibition of WEE1 by AZD1775 synergistically enhances CX-5461 mediated DNA damage and induces cytotoxicity in glioblastoma. (PubMed, Tissue Cell) - "Consequently, these results suggest that CX-5461 inhibited GBM progression by stabilizing G4, causing replication stress and exacerbating DNA damage. Targeting G4 structures, especially when combined with checkpoint inhibitors, provides a hopeful therapeutic approach to improve the effectiveness of GBM therapy."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

WEE1 inhibitor exerts synergistic effect with KRAS G12C inhibitor via MYBL2-RRM2 axis in KRASG12C-mutant lung cancer. (PubMed, Cell Death Dis) - "Here, we demonstrate that the WEE1 kinase inhibitor (WEE1i), Adavosertib, can sensitize the effect of G12Ci through the MYBL2-RRM2 axis, which is associated with poor prognosis in lung cancer...We also observed marked effects of the combination therapy in tumor xenografts models. Collectively, these results uncover the WEE1 kinase inhibitors, some of which are available clinically, as effective enhancers for G12Ci therapy."

Journal • Lung Cancer • Oncology • Solid Tumor • KRAS • MYBL2 • RRM2

WEE1 inhibitor exerts synergistic effect with KRAS G12C inhibitor via MYBL2-RRM2 axis in KRASG12C-mutant lung cancer (Nature) - "Here, we demonstrate that the WEE1 kinase inhibitor (WEE1i), Adavosertib, can sensitize the effect of G12Ci through the MYBL2-RRM2 axis, which is associated with poor prognosis in lung cancer. Overexpressing the MYBL2-RRM2 axis or supplementing the products of the RRM2 enzyme, dNTPs/dNs, can partially reverse this synergistic inhibitory effect. We also observed marked effects of the combination therapy in tumor xenografts models. Collectively, these results uncover the WEE1 kinase inhibitors, some of which are available clinically, as effective enhancers for G12Ci therapy."

Preclinical • Lung Cancer

Evaluation of pleural mesothelioma sensitivity to targeted DNA damage response inhibitors (EACR 2025) - "Long-term cell proliferation assays lasting 7 to 15 days were conducted using various concentrations of the following DDR inhibitors: berzosertib and ceralasertib (ATR inhibitors), AZD0156 (an ATM inhibitor), olaparib (a PARP inhibitor), adavosertib (a WEE1 inhibitor), and rabusertib (a CHEK1 inhibitor). These results represent a preclinical rationale for designing clinical trials with DDR for MPM patients."

Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Sarcoma • Solid Tumor • BAP1 • RAD51

Targeting the DNA damage response prevents regrowth of colorectal peritoneal metastasis-derived organoids following treatment with mitomycin C. (EACR 2025) - "We tested whether inhibitors of the DNA damage response (DDR) could prevent recurrence in an in vitro HIPEC model.Material and Peritoneal metastasis-derived organoids (PMDOs; n=10) were treated with inhibitors of ATR (berzosertib, ceralasertib, elimusertib), CHK1 (rabusertib), and WEE1 (adavosertib) alone, and in combination with MMC, oxaliplatin, or irinotecan. PMDOs can be completely eradicated if MMC treatment is followed by inhibition of ATR or other DDR kinases. DDR inhibitors may, therefore, have value in the adjuvant treatment of peritoneal metastases following CRS-HIPEC."

Colorectal Cancer • Oncology • Solid Tumor • CHEK1

Phase 2 study of Wee1 inhibitor adavosertib in recurrent uterine carcinosarcoma. (PubMed, Gynecol Oncol Rep) - "In this phase II trial of 9 patients with TP53-mutated UCS, adavosertib demonstrated limited activity. However, future studies of molecular alterations and combinatorial strategies continue to be of interest in UCS with limited treatment options."

Journal • P2 data • Carcinosarcoma • Fatigue • Oncology • Sarcoma • Solid Tumor • TP53

Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells. (PubMed, Discov Oncol) - "The combination of asciminib and WEE1 inhibition demonstrated greater efficacy than either drug alone, suggesting a novel therapeutic strategy for treating CML. These findings provide insights into overcoming TKI resistance and highlight a promising approach for future clinical applications."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ABL1 • PKMYT1 • WEE1

Solubility Modeling for Key Organic Compounds Used in Adavosertib (Anticancer API) Manufacturing. (PubMed, ACS Omega) - "The present paper has thus employed the Non-Random Two-Liquid Segment Activity Coefficient (NRTL-SAC) model to describe the solubility of six organic compounds used in the production of an experimental anticancer drug, Adavosertib (specifically: AZD1775 Adavosertib Maleate, AZD1775 Aniline Maleate, AZD1775 Nitropip, AZD1775 Hydroxymethylsulfanyl, AZD1775 Bromopyridine.HBr, and AZD1775 Pyrimidine). The NRTL-SAC model has also been employed to estimate the melting temperature and enthalpy of fusion of these compounds, circumventing various difficulties arising in direct measurements (e.g., endothermic/exothermic phenomena near the melting point)."

Journal • Oncology

Dual treatment with Val-083 and AZD1775 shows potent anti-tumor activity in diffuse midline glioma models. (PubMed, NPJ Precis Oncol) - "H3K27M diffuse midline gliomas (DMG) are characterized by p53 mutations and hypomethylation of MGMT, a DNA-repair enzyme, leading to resistance towards chemotherapeutic agents such as temozolomide (TMZ). In vivo, the combination of both drugs led to significant reduction in tumor growth in zebrafish xenograft models and prolongation of survival in mice xenograft models. Our findings indicate that Val-083 and AZD1775 in combination demonstrate promising efficacy in DMGs, providing a clinical rationale for positioning these arms in future therapies."

Journal • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • CDK1 • MGMT • TP53

Matrix Stiffness Influences Drug Resistance to Gemcitabine Analog and AZD 1775 Combination in PDAC Organoids. (PubMed, medRxiv) - "AZD 1775 enhances the efficacy of Gemcitabine-8C at non-toxic doses, demonstrating its potential for overcoming PDAC treatment resistance. The cell origin and tumor microenvironment plays a key role in modulating drug response, highlighting the need for microenvironment and individualized-targeted strategies."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Mechanisms of AICAr-Induced Acute Myeloid Leukemia Differentiation: Role of Ribonucleotide Metabolism and Replication Stress (EACR 2025) - "We also found that cytarabine (AraC), a standard chemotherapy agent, promotes differentiation via replication stress and Chk1 activation, a mechanism shared with pyrimidine synthesis inhibitors...Inhibition studies were conducted using COH29 and hydroxyurea (HU) as inhibitors of ribonucleotide reductase (RNR), MK1775 as a Wee1 inhibitor, and siRNA targeting Wee1.Result and Metabolomic analysis revealed that pyrimidine and purine nucleotides were among the most differentially regulated metabolites, decreasing in brequinar- and AICAr-treated samples while increasing in AraC-treated samples... Our findings suggest that ribonucleotide metabolism regulates AML differentiation, with Wee1 and RNR activation occurring downstream of replication stress."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CHEK1 • RRM2

Targeting WEE1 Kinase for Breast Cancer Therapeutics: An Update. (PubMed, Int J Mol Sci) - "Adavosertib's clinical promise was challenged by inter-individual variations in response and side effects. Because of these promising preclinical outcomes, other WEE1 kinase inhibitors (Azenosertib, SC0191, IMP7068, PD0407824, PD0166285, WEE1-IN-5, Zedoresertib, WEE1-IN-8, and ATRN-1051) are being developed, with several currently being evaluated in clinical trials or as an adjuvant to chemotherapies...Reliable predictors of clinical responses based on mechanistic insights remain an important unmet need. Herein, we review the role of WEE1 inhibition therapy in breast cancer."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC25C • CDK1 • CDK2 • GNRP • PKMYT1 • STING

Anti-cancer drug sensitivity testing and preclinical evaluation of the anti-cancer potential of WEE1 inhibitor in triple-negative breast cancer patient-derived organoids and xenograft models. (PubMed, Breast Cancer Res) - "PDOs, PDXOs, and PDXs, which maintained the immunological properties of TNBC patient, provide a scientific rationale for future WEE1-targeted clinical trials in TNBC. PDOs and PDXOs represent cost- and time-effective surrogates for predicting prioritized personalized therapy."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Transplantation • Triple Negative Breast Cancer • CASP3 • CASP7 • CDK1 • EGFR • PRKDC • VIM • WEE1

Transcriptomic Analyses of Ovarian Clear Cell Carcinoma Spheroids Reveal Distinct Proliferative Phenotypes and Therapeutic Vulnerabilities. (PubMed, Cells) - "Our studies showed that proliferative spheroid cells were sensitive to Wee1 inhibition by AZD1775, but the dormant spheroid cells showed a degree of resistance to AZD1775, both in terms of EC50 values and spheroid reattachment abilities. Thus, we identified biomarkers of dormant spheroids, including the G2/M checkpoint regulators Wee1, Cdc25c, and PLK1, and showed that, when compared to proliferating spheroid cells, the transcriptome of dormant OCCC spheroids is a source of therapeutic targets."

Journal • Clear Cell Carcinoma • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • CDC25C • GNRP • PLK1

AZD1775 in Women With Recurrent or Persistent Uterine Serous Carcinoma or Uterine Carcinosarcoma (clinicaltrials.gov) - P2 | N=49 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Jun 2026 ➔ Dec 2026 | Trial primary completion date: Jun 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Carcinosarcoma • Endometrial Serous Adenocarcinoma • Oncology • Sarcoma • Solid Tumor • Uterine Cancer

Characterization of m6A-Related Genes in Tumor-Associated Macrophages for Prognosis, Immunotherapy, and Drug Prediction in Lung Adenocarcinomas Based on Machine Learning Algorithms. (PubMed, FASEB J) - "Furthermore, it was predicted that drugs such as BRD9876 and MK-1775 would demonstrate therapeutic efficacy in treating LUAD, and drugs showing potential binding with DUSP2, ZNF331, FLT, and LYZ were identified...Our study offers valuable insights into the biological significance of MMRGs, shedding light on novel mechanisms of tumor development and immune evasion in LUAD. Furthermore, our findings have identified potential biomarkers, drug candidates, and therapeutic targets that may improve the management of LUAD in the future."

Biomarker • IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • DUSP2 • HMGB2 • NR4A2

Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft models. (PubMed, Front Oncol) - "Fifty-one PDX models (46 with and 5 without NCI-MPACT aMOIs) were tested against both the arm that would have been assigned in the NCI-MPACT trial as well as every other study regimen: (1) veliparib plus temozolomide or (2) adavosertib plus carboplatin (targeting the DNA repair pathway); (3) everolimus (targeting the PI3K pathway); and (4) trametinib (targeting the RAS/RAF/MEK pathway)...Eleven of 50 models (22%) treated with veliparib plus temozolomide responded according to one or both metrics, as did 2/47 models (4.2%) treated with adavosertib plus carboplatin, and 2/46 models (4.3%) treated with trametinib; no models responded to erlotinib...This prospective preclinical study confirmed the modest response rates in the NCI-MPACT clinical trial. Substantial responses to temozolomide suggest that this drug represents an effective treatment for patients with MGMT deficiency, regardless of cancer type."

Journal • Preclinical • Oncology

Adavosertib Yields Preliminary Safety Concerns, Antitumor Activity in USC (Oncology Nursing News) - P2b | N=109 | NCT04590248 | Sponsor: AstraZeneca | "Heavily pretreated patients with uterine serous carcinoma experienced preliminary antitumor activity with adavosertib (AZD1775), but the WEE1 inhibitor was not well tolerated when administered once daily at 300 mg...in patients from the full analysis set, the objective response rate (ORR) among patients evaluable for response per blinded independent central review (BICR; n = 104) was 26.0% (95% CI, 17.9%-35.5%), with 1.0% and 25.0% of patients achieving complete responses (CRs) and partial responses (PRs), respectively. Those in the full analysis set evaluable for response per investigator assessment (n = 109) had an ORR of 21.1% (95% CI, 13.9%-30.0%), including CR and PR rates of 1.8% and 19.3%, respectively."

P2b data • Uterine Cancer

Potential novel interventions of oncohistones, epigenetic modifications, and RNA processing machinery in betel-nuts related HNSCC in Taiwan (AACR 2025) - "PI3K/AKT/mTOR interventions, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, p53 reactivator, MDM2 inhibitor, SHP2 inhibitor, PARP7 inhibitor, IAP inhibitor, GLS1 inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and modulation of stemness & PD1/PDL1 pathway...Disrupting NSD1 in HNSCC cell lines led to CpG hypomethylation & enhanced cisplatin sensitivity. TW2.6 used to test (1)in vitro drug sensitivity to (a)Chemical Modulators of Splicing; (b)PRMT5 inhibitor; (c)CDK9 inhibitor, EZH2i, DNMT3i, BRD/BET4i, and HDACi; (d)NSD1/SETD2 inhibitor; (e)METTL3 inhibitor; (2)synergistic effects with other therapies by MTT assay, colony..."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • AKT1 • ALK • ARID1B • ATM • AXL • BRD4 • CCND3 • CDK12 • CXCR4 • DDR2 • EPHB1 • FAT1 • FGF10 • FGFR • FLCN • HRAS • KDM5A • KDR • METTL3 • MITF • NSD1 • PDGFRB • PIK3CA • RICTOR • RPS6KB1 • SDHA • SETD2 • SOX9 • STK11 • TERT • TIPARP • TMB • TNFAIP3

OVERCOMING DRUG RESISTANCE BY TARGETING THE WEE1-MYC AXIS IN GASTRIC ADENOCARCINOMA (DDW 2025) - "Functional studies supported these findings, as WEE1 inhibition through siRNA or the pharmacological inhibitor MK1775 reduced MYC protein levels and transcriptional activity, whereas WEE1 overexpression induced MYC signaling and increased the expression of its downstream targets BCL2 and BCL2L1. Therapeutically, preliminary findings indicated that oxaliplatin-resistant GC cell lines, AGS and MKN45, which exhibited higher WEE1 expression, were particularly sensitive to WEE1 inhibition... These results suggest that WEE1 plays a pivotal role in MYC-driven oncogenesis and highlight its potential as a promising therapeutic target in GC, particularly in cases resistant to conventional treatments. While these findings are preliminary, they provide strong rationale for further exploration of WEE1 inhibition, especially in combination with Afatinib, in GC therapy."

IO biomarker • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • E2F1 • WEE1

TARGETING C-MYC FOR DEGRADATION THROUGH WEE1 INHIBITION IN ESOPHAGEAL ADENOCARCINOMA (DDW 2025) - "WEE1 inhibition significantly reduced MYC's half-life, while proteasomal inhibition with MG 132 rescued MYC protein decrease induced by WEE1 inhibition, confirming that WEE1 stabilizes MYC by preventing proteasome-mediated degradation. 892 FDA-approved compounds were screened for synergy with MK 1775... In conclusion, these findings demonstrate that WEE1 overexpression reinforces MYC-driven oncogenic programs by inhibiting GSK3β activity. Targeting WEE1 induces significant MYC degradation, leading to reduced cancer cell viability, highlighting its potential as a therapeutic strategy."

Esophageal Adenocarcinoma • Esophageal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • MYC • WEE1

AZD1775: effect of monotherapy or EDP-M combination in the treatment of ACC preclinical models. (ESPE-ESE 2025) - "The current treatment for advanced ACC is represented by EDP-M (etoposide, doxorubicin, cisplatin + mitotane), but its efficacy is limited and new therapeutic approaches are needed. Furthermore, the combined therapy AZD1775+EDP-M synergistically reduced cell proliferation and viability in vitro, impaired tumor growth of H295R xenografts, and was efficient even upon re-exposure of cells derived from treated mice. Our data support AZD1775 as a novel therapeutic option for ACC, as well as its combination with EDP-M as a useful strategy to enhancing drug efficacy, possibly reducing the therapeutic dose, minimizing side effects and preventing the development of drug resistance."

Monotherapy • Preclinical • Adrenal Cortex Carcinoma • Endocrine Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

Enhancing antitumor immunity by targeting cancer associated fibroblasts with radiation and ATM inhibition (ESTRO 2025) - "Cells were treated with radiation (2, 6 or 18 Gy) and inhibitors targeting ATR (VE-822), ATM (AZD1390), CHK1 (LY2606368) and WEE1 (AZD1775). This study demonstrates that combining radiation with ATM inhibition can effectively target CAFs, inducing an IFN-I response. Beyond the well-established radiosensitizing effects of ATM inhibition, our findings reveal a potential novel role for ATM inhibitors in reprogramming NSCLC-CAFs into an immune-activating phenotype. This dual mechanism represents a promising approach to enhance radiotherapy-immunotherapy synergies by reducing the immunosuppressive influences of the tumor microenvironment."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CAFs • CDKN1A • CHEK1 • IFNB1

Dual inhibition of PKMYT1 and WEE1 kinases as a targeted therapy for ATIP3-deficient breast cancers (AACR 2025) - "Inhibiting WEE1 with AZD1775 selectively compromises ATIP3-deficient cells by exacerbating DNA damage, mitotic abnormalities and chromosome pulverization, ultimately leading to cell death...This dual-targeting strategy holds promise for improving outcomes in aggressive breast cancer subtypes. Furthermore, our work highlights the potential of ATIP3 as a predictive biomarker for patient stratification and the rational development of personalized therapies."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PKMYT1