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

Safety and Efficacy of Ceralasertib plus Olaparib for Advanced/Metastatic Triple-Negative Breast Cancer in Three Molecular Strata: The Phase II VIOLETTE Study. (PubMed, Clin Cancer Res) - P2 | "In patients with advanced PARP inhibitor-naïve non-HRRm TNBC, ceralasertib + olaparib significantly improved ORR versus olaparib. However, clinical significance is limited without improvement in PFS."

Journal • P2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HRD

Phase II Study of Adavosertib in Patients With Tumors Containing BRCA1 and BRCA2 Mutations: Results From the NCI-MATCH ECOG-ACRIN Cancer Research Group (EAY131) Subprotocol Z1I. (PubMed, JCO Precis Oncol) - "In heavily pretreated, advanced solid tumor patients with PV in BRCA1/2, adavosertib treatment resulted in low ORR, and this trial did not meet the primary end point."

Journal • P2 data • Fatigue • Hematological Disorders • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2

ADAGIO: A Phase IIb, Open-Label, Single-Arm, Multicenter Study Assessing the Efficacy and Safety of Adavosertib (AZD1775) as Treatment for Recurrent or Persistent Uterine Serous Carcinoma. (PubMed, J Clin Oncol) - P2b | "Adavosertib showed some antitumor activity in patients with recurrent/persistent USC. However, at 300 mg once daily dosing, it was not well tolerated in this population. Exploratory biomarker studies suggest CCNE1/cyclin E1 expression may enrich for response to Wee1 inhibition in USC."

Clinical • Journal • P2b data • Endometrial Serous Adenocarcinoma • Fatigue • Hematological Disorders • Neutropenia • Oncology • Uterine Cancer • CCNE1

WEE1 Inhibition as a Novel Therapeutic Strategy in Cutaneous T-Cell Lymphoma. (PubMed, Cancers (Basel)) - "In a preliminary xenograft experiment, adavosertib slowed MyLa tumour growth. These preclinical data identify WEE1 as a therapeutic target in CTCL and support further preclinical and early-phase clinical evaluation of adavosertib in this disease."

Journal • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • CD4 • CDK1

VIOLETTE: Randomised Phase 2 Study of Olaparib (ola) + Ceralasertib (cer) or Adavosertib (ada) vs Ola Alone in Patients (pts) With Metastatic Triple-Negative Breast Cancer (mTNBC) (ESMO-BC 2022) - P2 | "Cer+ola had a manageable safety profile consistent with known profiles of each. Further analyses may identify pts likely to benefit from each treatment."

Clinical • P2 data • Anemia • Breast Cancer • Hematological Disorders • Oncology • Solid Tumor • Triple Negative Breast Cancer • HRD

Comprehensive Profiling of OTSSP167 Action in Adrenocortical Carcinoma. (PubMed, Endocrinology) - "Together these findings establish the feasibility of using OTSSP167 in ACC, especially in TP53 mutant ACC tumors. In addition, this study demonstrates the possibility of targeting the early adaptive response subsequent to exposure to OTSSP167 treatment. Our findings provide strong rationale for a future phase I clinical trial in ACC."

Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • TP53

WEE1 kinase in cancer: Molecular mechanisms and inhibitor insights. (PubMed, EXCLI J) - "We have also summarized the clinical development of major WEE1 inhibitors such as adavosertib, azenosertib (ZN-c3), and Debio 0123. See also the graphical abstract(Fig. 1)."

Journal • Review • Oncology • Targeted Protein Degradation • CDK1 • TP53

NCI10329: Phase Ib Sequential Trial of Agents against DNA Repair (STAR) Study to investigate the sequential combination of the Poly(ADP-Ribose) Polymerase inhibitor (PARPi) olaparib (ola) and WEE1 inhibitor (WEE1i) adavosertib (ada) in patients (pts) with DNA Damage Response (DDR)-aberrant advanced tumors, enriched for BRCA1/2 mutated and CCNE1 amplified cancers (AACR-NCI-EORTC 2022) - P1 | "RP2D was ola 300mg BID D1-5, 15-19 + ada 300mg OD D8-12, 22-26; Q28 days. Planned expansion cohorts include (1) pts with BRCA1/2m tumors with intrinsic PARPi resistance and (2) pts with DDR mutated tumors with acquired PARPi resistance."

Clinical • Late-breaking abstract • P1 data • Breast Cancer • Gastric Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • ARID1A • BRCA1 • BRCA2 • CCNE1 • MUC16 • PALB2 • RAD51

A Phase I Study of Nab-Paclitaxel, Gemcitabine and AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas: ECOG-ACRIN EA2131. (PubMed, Clin Colorectal Cancer) - P2 | "The combination of nab-paclitaxel, gemcitabine, and AZD1775 was determined to be too toxic when administered in patients with metastatic or locally advanced, unresectable pancreatic adenocarcinoma."

Journal • P1 data • Cardiovascular • Febrile Neutropenia • Heart Failure • Hematological Disorders • Mucositis • Neutropenia • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Stomatitis • Thrombocytopenia

A phase II trial of AZD1775 plus carboplatin-paclitaxel in squamous cell lung cancer (SqCLC). (ASCO 2024) - P2 | "Background: In pre-clinical studies, WEE1 inhibitors have displayed synergy with cisplatin in lung cancer cell lines. The study met its primary endpoint with a median PFS of 4.8 months with the combination of Adavosertib with carboplatin and paclitaxel. However, the study regimen achieved similar response rates and median PFS of platinum-doublet combination when comparing to historical data from phase II/III trials. Although the combination was safe, over a third of patients experienced grade 3 AEs, and 10% required dose reductions or delays due to AEs."

IO biomarker • P2 data • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Introduction to Single-Cell Physiologically-Based Pharmacokinetic (scPBPK) Models. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The AZD1775 model simulations indicated a large degree of single-cell drug concentration heterogeneity, whereas those for midazolam did not due to high membrane transport relative to metabolism. scPBPK models offer a means to probe cellular pharmacokinetics compatible with modern omic technologies and may be extended to pharmacodynamic models."

Journal • PK/PD data

Selective Macrocyclic WEE1 Kinase Inhibitors with Strong Efficacy against Patient-Derived Colorectal Cancer Organoids. (PubMed, J Med Chem) - "The clinical candidate AZD1775 (1) failed to progress past Phase II trials because of patient tolerability issues, likely due to off-target inhibition of polo-like kinase 1 (PLK1)...Against patient-matched normal colon vs primary CRC organoids, 2 potently and selectively treated CRC, as well as enhanced DNA damage compared to 1. Finally, the X-ray cocrystal structure of 2 bound to WEE1 validated its computationally predicted bioactive binding mode."

Journal • Colorectal Cancer • Oncology • Solid Tumor • PLK1

Consensus subtypes and a generalizable prognostic signature defined by an R-loop score in hepatocellular carcinoma: Multi-omics analyses pinpoint KIF2A-positive proliferative tumor cells. (PubMed, Pathol Res Pract) - "R-loop-associated programs define a clinically relevant prognostic axis in HCC, with KIF2A-positive proliferative tumor cells representing a key high-risk cellular source and potential therapeutic vulnerability."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CCNB2 • CDC20

Targeting WEE1 kinase: an integrated machine learning-cheminformatics framework for ultra-large-scale virtual screening and novel inhibitor discovery. (PubMed, J Comput Aided Mol Des) - "Although clinical inhibitors such as adavosertib have demonstrated therapeutic potential, challenges, including selectivity constraints, dose-limiting toxicities, and emerging resistance, highlight the need to expand the structural diversity of WEE1-targeting chemotypes...Preliminary in vitro evaluation of one SPECS-derived compound (AJ-292/13095349) demonstrated antiproliferative activity in triple-negative breast cancer (TNBC) models. Collectively, this study establishes an efficient computational hit identification framework for ultra-large screening and reports structurally distinct starting points for WEE1-targeted oncology drug discovery."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PLK1

Combination AURKA and WEE1 inhibition exhibits efficacy in EGFR or pan-ERBB inhibitor resistant head and neck squamous cell carcinoma. (PubMed, Cancer Res Commun) - "To identify strategies to overcome resistance in HNSCC, we developed HNSCC cell models that were treatment-naïve parental, or selected for resistance to the EGFRi erlotinib, or the ERBBi afatinib. Based on increased AURKA dependence, we compared combination of VIC-1911 with adavosertib, an inhibitor of the cell cycle checkpoint regulator WEE1, in parental versus resistant models. These showed a combination effect both in vitro and in vivo, that was retained in ERBBi-resistant xenografts, suggesting the potential value of combined AURKA and WEE1 inhibitor use in patients with ERBB inhibitor-resistant HNSCC."

Journal • Head and Neck Cancer • Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • AURKA • EGFR • NEDD9

Combined Inhibition of Wee1 and Checkpoint Kinases Synergistically Provokes S-Phase Progression and Mitotic Entry, and Promotes Cell Death Under Heat Stress. (PubMed, Genes Cells) - "Moreover, the combination of MK-1775 and AZD-7762 abrogated G2 arrest and enhanced HS-induced cell death in MG-63 and HSC-3 cells. These findings indicate that simultaneous inhibition of Wee1 and Chk1/2 could be a promising strategy for augmenting the therapeutic efficacy of hyperthermia."

Journal • Oncology

SYNGR2 as a Multifaceted Biomarker in Hepatocellular Carcinoma Linking Prognosis, Immune Microenvironment and Therapeutic Response. (PubMed, Technol Cancer Res Treat) - "Bioinformatic predictions revealed that SYNGR2-high tumors were more sensitive to MK-1775 (DNA damage inhibitor) and paclitaxel, whereas SYNGR2-low tumors were sensitive to JAK1/IAP inhibitors. Critically, plasmid-mediated overexpression of SYNGR2 in Huh7 cells significantly sensitized them to MK-1775, while siRNA-mediated knockdown of SYNGR2 in Hep3B cells conferred significant resistance, establishing a causal role for SYNGR2 in modulating sensitivity to this WEE1 inhibitor.ConclusionSYNGR2 has emerged as a multifaceted biomarker candidate in HCC, associated with prognosis, an immunosuppressive microenvironment, and differential therapeutic responses. Its integration into clinical models could enhance prognostic stratification and guide personalized treatment strategies, particularly in selecting patients for DNA damage-targeting agents."

Biomarker • IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • JAK1 • PD-1 • PD-L1 • SYNGR2

Targeting cell cycle vulnerability in clear cell ovarian cancer via WEE1 inhibition (ESMO-Gynae 2026) - "Both CCOC and HGSOC cell lines were treated with increasing concentrations of the WEE1i adavosertib...Whether ARID1A loss further enhances benefit from WEE1 inhibition merits further investigation. Our data support a trial of WEE1 inhibition in CCOC patients."

Gynecologic Cancers • Oncology • Ovarian Cancer • Ovarian Clear Cell Cancer • Solid Tumor • ARID1A • CCNE1

Combination Treatment Targeting Cancer Stem Cell Subpopulation Reverting Chemoresistance in Germ Cells Tumors (EACR 2026) - "Material and A broad panel of parental and cisplatin-resistant (CisR) isogenic GCT cell lines was analyzed for TACSTD2 (TROP-2) expression by RT-qPCR, and sensitivity to sacituzumab govitecan was assessed at day 3 using an endpoint luminescence assay. To explore strategies for overcoming chemoresistance, combination treatments were performed with a panel of targeted pathway inhibitors affecting cell cycle, DNA damage response, transcriptional regulation, and oncogenic signaling (Tuvusertib [CDK7 inhibitor], Ceralasertib [ATR inhibitor], Adavosertib [WEE1 inhibitor], Simvastatin, Copanlisib, ABVV-744, Cyclosporin A, Dasatinib, Crizotinib, Tozasertib, Alpelisib, Selumetinib) to evaluate potential synergistic effects.Result and We focused on the transmembrane glycoprotein TROP-2 (trophoblast cell surface antigen 2), involved in proliferation, migration, and invasiveness, which is overexpressed in multiple solid tumors... Our findings support further investigation of..."

Cancer stem • Clinical • Germ Cell Tumors • Oncology • Solid Tumor • Testicular Cancer • TACSTD2

MiR-22 targets the G2/M checkpoint inhibitor WEE1 and represents a biomarker of TACE response in hepatocellular carcinoma (EACR 2026) - "The miR-22/WEE1 axis influenced the DNA damage response, with the WEE1 inhibitor adavosertib inducing mitotic catastrophe in HCC cells treated with doxorubicin under chemical hypoxia. Fold change of miR-22 levels represents a promising biomarker of nonresponse to TACE. If confirmed in independent cohorts, early increase of miR-22 may help to identify HCC patients with reduced benefit from TACE. The miR-22/WEE1 axis may serve as a potential therapeutic target for tailored strategies in HCC patients undergoing TACE."

Biomarker • Checkpoint inhibition • Hepatocellular Cancer • Oncology • Solid Tumor • MIR22 • WEE1

A Possibility of Synthetic Lethality: Wee1 Kinase as a Promising Treating Target for Cancer. (PubMed, Med Res Rev) - "Wee1 is the fastest progressing member in clinical research, and its inhibitors such as AZD-1775 and ZN-c3 are under clinical evaluation. We further summarize design principles for targeted degradation of Wee1 and outline combination strategies grounded in synthetic lethality, and we curate recent preclinical and ongoing clinical advances with discussion of biomarker-guided enrollment and dosing schedules. By linking structural mechanisms to pharmacology and clinical placement, this review provides an actionable framework for next-generation Wee1-directed drug design and translation in oncology."

Journal • Review • Oncology • Targeted Protein Degradation • PKMYT1 • TP53

Apoptosis-related gene model predicts the prognosis in patients with acute myeloid leukemia. (PubMed, Blood Sci) - "In addition, high-risk patients exhibited significant enrichment in pathways related to TP53 dysfunction, mechanistic target of rapamycin complex 1 (mTORC1) signaling activation, and pro-inflammatory responses, which were closely correlated with NPM1c-FLT3 co-mutations. Decitabine, sunitinib, and MK-1775 were identified as potential therapeutic agents. In summary, we established a 5-ARG prognostic model that may facilitate risk stratification and inform therapeutic decision-making in AML."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CDC37 • DDIT4 • ENO1 • FLT3 • HSP90AB1 • SLC7A11 • TP53

Integrative Transcriptomics Identifies Ubiquitination-Related Genes BIRC2, COPS5, and TBK1 as Novel Biomarkers of T-Cell Dysregulation in Amyotrophic Lateral Sclerosis. (PubMed, J Inflamm Res) - "Adavosertib and MRS2211 were identified as potent modulators of TBK1 and BIRC2, respectively...qPCR validation confirmed significantly increased expression of these genes in patients with ALS (p<0.05). TURDEGs-mediated T cell dysfunction and ubiquitination imbalance play critical roles in ALS pathogenesis, unveiling novel biomarkers and potential personalized therapeutic targets."

Biomarker • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Targeted Protein Degradation • BIRC2 • CD4 • TBK1

Testing the Sequential Combination of the Anti-cancer Drugs Olaparib Followed by Adavosertib (AZD1775) in Patients With Advanced Solid Tumors With Selected Mutations and PARP Resistance, STAR Study (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2026 ➔ Dec 2026

Trial completion date • Oncology • Solid Tumor • BRCA1 • BRCA2 • BRIP1 • CD4 • FANCA

Testing the Addition of an Anti-cancer Drug, Adavosertib, to Radiation Therapy for Patients With Incurable Esophageal and Gastroesophageal Junction Cancers (clinicaltrials.gov) - P1 | N=4 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Esophageal Adenocarcinoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma