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

Cyclin E1 as a driver of oncogenesis; high grade serous ovarian cancer as an exemplar. (PubMed, Crit Rev Oncol Hematol) - "The WEE1 inhibitor adavosertib and the CDK2 inhibitor INCB123667 achieved response rates of 53% and 33% respectively in platinum-resistant ovarian cancer patients whose tumours overexpressed cyclin E1. Targeting of cyclin E dysregulation via a synthetic lethality approach is therefore a key area of focus for improving treatment strategies in HGSOC and other cancers with high unmet clinical need. In this review we discuss the functions of cyclin E1, mechanisms and consequences of dysregulation, and strategies for therapeutic exploitation of cyclin E1 dysregulated tumours, combining fundamental biology with clinical perspectives."

Journal • Review • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1

Investigating the role of CDKN2B in glioblastoma (SNO 2025) - "We generated double knockouts of CDKN2A and CDKN2B in M059K cells and obtained modest but significant increases in sensitivity to both the CHK1/2 inhibitor Prexasertib and the WEE1 inhibitor Adavosertib, another inhibitor of the G2/M checkpoint. This demonstrated that the additional loss of CDKN2B along with CDKN2A loss and TP53 mutation was necessary to sensitize these cells to G2/M checkpoint inhibition. This work suggests that inactivation of both CDKN2A and CDKN2B is necessary to accurately model this homozygous deletion."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • CDKN2A • CDKN2B • CHEK2

PLK1 or WEE1 inhibition targets homologous recombination repair proficiency in BRCA1/2 wild-type high-grade serous ovarian cancer. (PubMed, Cell Death Dis) - "We evaluated cell cycle-targeted strategies to overcome HR-proficient chemoresistance using either volasertib (a selective PLK1 inhibitor) or adavosertib (a potent WEE1 inhibitor) in BRCA-WT/HR-proficient and BRCA-mutant/HR-deficient HGSOC models. Functional and xenograft models confirmed selective vulnerability of BRCA-WT tumors to either PLK1 or WEE1 inhibition. Our work highlights a mechanistic framework linking cell cycle checkpoint inhibition to DNA repair pathway selectivity, providing a rationale for targeting mitotic regulators in HR-proficient ovarian cancer-a subgroup with high clinical unmet need."

Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • HRD • PLK1 • RAD51

Matrix stiffness influences drug resistance to gemcitabine analog and AZD 1775 combination in PDAC organoids. (PubMed, PLoS One) - "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

A phase i/ii single-arm trial of azenosertib (zn-c3) combined with carboplatin and pembrolizumab in patients with metastatic triple-negative breast cancer (zap-it) (SABCS 2025) - "A phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in 34 patients with mTNBC treated with 0-1 prior lines of chemotherapy showed an ORR of 26% (Keenan. A maximum of 78 patients will be enrolled. To our knowledge this is the first and only ongoing study testing the combination of a WEE1 inhibitor with carboplatin and a checkpoint inhibitor for the treatment of breast cancer."

Clinical • IO biomarker • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDK1 • HER-2 • PD-L1 • WEE1

Investigating the role of CDKN2B in glioblastoma (WFNOS 2025) - "We generated double knockouts of CDKN2A and CDKN2B in M059K cells and obtained modest but significant increases in sensitivity to both the CHK1/2 inhibitor Prexasertib and the WEE1 inhibitor Adavosertib, another inhibitor of the G2/M checkpoint. This demonstrated that the additional loss of CDKN2B along with CDKN2A loss and TP53 mutation was necessary to sensitize these cells to G2/M checkpoint inhibition. This work suggests that inactivation of both CDKN2A and CDKN2B is necessary to accurately model this homozygous deletion."

Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Solid Tumor • CDKN2A • CDKN2B • CHEK2

WEE1 inhibition delays resistance to CDK4/6 inhibitor and antiestrogen treatment in ER+ MCF7 cells (Nature) - "We treated ER+ MCF7 breast cancer cells with palbociclib alternating with a combination of fulvestrant and WEE1 inhibitor AZD1775 for 12 months. We found that the alternating treatment delayed the development of drug resistance to palbociclib and fulvestrant compared to monotherapies. We developed a mathematical model that can simulate cell proliferation under monotherapy and alternating drug treatments. Finally, we showed that the mathematical model can be used to minimize the number of fulvestrant plus AZD1775 treatment periods while maintaining its efficacy."

Preclinical • Estrogen Receptor Positive Breast Cancer

Drug repurposing identifies novel Wee1 kinase inhibitors for triple negative breast cancer therapeutics. (PubMed, Eur J Med Chem) - "Optimal dosing ratios of 1:1 for adavosertib-cisplatin and 1:2 for dactolisib-cisplatin were identified, underscoring effective, dose-dependent synergy in these combinations. Dactolisib and adomeglivant show promise as Wee1 kinase inhibitors in TNBC, with dactolisib exhibiting superior potency, and their synergistic potential in combination therapies, such as with cisplatin, highlighting avenues for future clinical development."

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

Indicators of Response to the Wee1 Inhibitor Adavosertib in Acute Myeloid Leukemia (ASH 2023) - P1/2 | "Wee1 is a nuclear kinase that regulates cell cycle progression by inhibiting Cdk1, which is essential for G2 to M phase transition. In addition, high CD34 expression in resistant samples suggests that immature stem and progenitor cells may be less susceptible to Wee1i. In summary, targeting of Wee1 in AML – as studied in NCT05682170 azenosertib study - may be effective for a molecularly defined subset of patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AFDN • CD34 • CDC37 • CDK1 • CDK2 • GLI2 • S100A16

Decitabine Synergizes with Replication Checkpoint Inhibitors in TP53-Mutated Acute Myeloid Leukemia (ASH 2024) - "Prior reports suggest that DNA methyltransferase inhibitors (DNMTi), such as decitabine and azacitidine, form covalent DNA-DNMT1 adducts and invoke a DNA damage response (DDR) characterized by activation of the ATR-CHK1 pathway, including in TP53MT AML samples...Similar results were obtained from decitabine (EC50 = 300 ± 100 nM) and ceralasertib (CI 0.54), adavosertib (CI 0.67), MK-8776 (CI 0.52), and prexasertib (CI 0.81) in annexin V assays.These combinations were further evaluated (SubG1 assays) in an isogenic pair of Molm13 and Molm13 TP53-/- cell lines...Combination treatment was antagonistic with ceralasertib (CI 2.2), additive with prexasertib (CI 1.0), and synergistic with adavosertib (CI 0.88).ConclusionsIn multiple cell lines and diverse primary AML samples, decitabine activated the ATR-CHK1 DDR pathway and synergized with ATRi, CHK1/2i, and WEE1i. Amongst these, only the combination of decitabine plus adavosertib exhibited synergy across all three models,..."

Checkpoint inhibition • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • DNMT1

ATR Inhibitor Elimusertib Suppresses Drug Persister Clones in TP53-Mutated Acute Myeloid Leukemia Via CGAS-Sting-Mediated Cell Death (ASH 2024) - "Among these, the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor elimusertib (BAY1895344) effectively inhibited TP53 mut AML DTPCs at low doses, similar to known inhibitors the CHK1 inhibitor (SRA737) and the Wee1 inhibitor (Adavosertib)...Furthermore, the triple combination treatment of cytarabine, idarubicin, and elimusertib effectively suppressed DTPC formation in TP53 mut AML cell lines...This consequently results in cGAS-STING-mediated cell death following irreparable DNA replication stress accompanied by p53 dysfunction. Our findings provide a basis for developing optimized treatment strategies for patients with TP53-mutant AML using the ATR inhibitor elimusertib."

Acute Myelogenous Leukemia • Ataxia • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Oncology • Primary Immunodeficiency • CDC25C • CDK1 • CDKN1A • CXCL10 • GNRP • IFI27 • IFIT1 • RSAD2 • SIGLEC1 • STAT1 • STING • TP53

A quantitative model-based approach for adavosertib dose selection in patients with uterine serous carcinoma. (PubMed, Br J Clin Pharmacol) - P2b | "The approach identifies risk factors that can aid in the decision to use a 250-mg monotherapy dose. This regimen may manage haematological toxicities across studies. A quantitative model-based approach predicts that reducing adavosertib doses minimizes risks, underscoring the need for dose adjustment."

Journal • Endometrial Serous Adenocarcinoma • Hematological Disorders • Neutropenia • Oncology • Uterine Cancer

Two Phase II Trials of Adavosertib, a Wee1 Inhibitor with Docetaxel or Carboplatin plus Pemetrexed in Non-small-cell Lung Cancer. (PubMed, Target Oncol) - P2 | "Both studies terminated early; the recurrent study after an interim analysis showed increased toxicity and limited efficacy, and the first-line study after a change in first-line standard of care."

Journal • P2 data • Fatigue • Hematological Disorders • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thrombocytopenia

Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status. (PubMed, Oncol Res) - "The efficacy of the mouse double minute 2 homolog (MDM2) inhibitor (HDM201) and the Wee1 G2 checkpoint kinase (Wee1) inhibitor (adavosertib) was confirmed in both p53 wild-type (p53 WT) and p53 mutant (p53 MT) GIST cells. Our results highlight the importance of p53 status in guiding GIST treatment. p53 WT tumors respond to MDM2 inhibitors, while p53 MT tumors show greater sensitivity to Wee1 inhibitors, supporting p53 pathway targeting as a promising strategy for GIST patients."

Journal • Preclinical • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • CDK1 • CDKN1A • PDGFRA • TP53

Plasma exosomal lncRNA-related signatures define molecular subtypes and predict survival and treatment response in hepatocellular carcinoma. (PubMed, Front Immunol) - "Risk model analysis predicted differential treatment responses: low-risk patients exhibited superior anti-PD-1 immunotherapy responses, whereas high-risk patients showed increased sensitivity to DNA-damaging agents (e.g., the Wee1 inhibitor MK-1775) and sorafenib. Plasma exosomal lncRNAs enable robust molecular subtyping, accurate prognostic stratification, and treatment response prediction in HCC. The ERG-centric classification system and validated 6-gene risk model provide clinically actionable tools for precision oncology."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Hepatocellular Cancer • Oncology • Solid Tumor • ADH1C • CTLA4 • KIF20A • MCM4 • NDRG1 • PD-L1 • RECQL4 • TGFB1 • TMB • TTN

ACR-2316 is a novel, differentiated, clinical-stage WEE1/PKMYT1 inhibitor designed by Acrivon's Generative Phosphoproteomics AP3 Platform for optimal pro-apoptotic pathway effects in tumor cells resulting in superior preclinical activity (AACR-NCI-EORTC 2025) - "In cellular TE assays, ACR-2316 displayed more potent WEE1 TE than all benchmark WEE1 inhibitors (azenosertib, adavosertib, Debio0123), while simultaneously targeting MYT1... WEE1 inhibitor-induced MYT1 activation constitutes a resistance mechanism that may limit the clinical efficacy of WEE1 inhibition. ACR-2316 is a potent, selective WEE1/MYT1 inhibitor that displays superior preclinical efficacy via its differentiated profile optimized by AP3 pathway-based structure-activity relationships in the intact cell. Acrivon's ongoing Phase 1 ACR-2316 monotherapy trial in solid tumors has already demonstrated clinical activity during dose escalation prior to reaching Recommended Phase 2 Dose."

Preclinical • Tumor cell • Oncology • Solid Tumor • BRAF • CDK1 • CDK2 • PKMYT1 • PLK1

Biomarker analyses of WEE1 inhibition in patients with refractory CCNE1 amplified solid tumors (AACR-NCI-EORTC 2025) - P2 | "Biomarker analyses using IHC, RNA-seq and WES showed WEE1 inhibition induced significantly expression of the immunosuppressive genes. Patients with immune-desert TME at baseline or on treatment responded poorly to WEE1 inhibition, supporting further exploration of WEE1 inhibition in combination with TME-modulated immunotherapy for the treatment of patients with CCNE1 amplified malignancies."

Biomarker • Clinical • IO biomarker • Oncology • Solid Tumor • CCNE1 • FKBP5 • MB • TGFB1 • TP53 • TSC22D3

Inducing mitotic catastrophe in high replicative stress castration resistant prostate cancer through inhibition of WEE1 (AACR-NCI-EORTC 2025) - " We determined the half-maximal inhibitory concentrations (IC₅₀) of two WEE1 inhibitors, AZD1775 (adavosertib) and ZN-c3 (azenosertib), in a panel of LNCaP-derived prostate cancer cell lines: LNCaP (parental), LNCaP-AR (androgen receptor amplification), and LNCaP-DKO (RB1 and TP53 double knockout). Our findings demonstrate that mCRPC models with G1 checkpoint mutations and inherently high replicative stress are more susceptible to WEE1i, revealing a potential predictive biomarker that can be leveraged for therapeutic efficacy."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CDK1 • RB1 • TP53

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 2025 ➔ Sep 2026

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

Preclinical evaluation of the antitumoral efficacy of Wee1 inhibitor AZD1775 in adrenocortical carcinoma. (PubMed, Pharmacol Res) - "Current therapy for advanced adrenocortical carcinoma (ACC) is represented by EDP-M (etoposide, doxorubicin, cisplatin + mitotane), but its efficacy is limited and new approaches are needed. Interestingly, Myt1 increase after AZD1775 treatment in primary ACC cells was reverted by EDP-M cotreatment. Overall, our data in in vitro and in vivo preclinical ACC models support AZD1775 as a promising ACC therapeutic option, and its combination with EDP-M as a useful strategy to enhance drug efficacy, reduce cortisol secretion, prevent drug resistance and minimize side effects by reducing the therapeutic dosage."

Journal • Preclinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • PKMYT1

NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=6452 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Biomarker • Trial completion date • Trial primary completion date • Bladder Cancer • Brain Cancer • Breast Cancer • Cervical Cancer • Colon Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Glioblastoma • Glioma • Head and Neck Cancer • Hematological Malignancies • Hormone Receptor Positive Breast Cancer • Kidney Cancer • Liver Cancer • Lung Cancer • Lymphoma • Melanoma • Multiple Myeloma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Refractory Ovarian Cancer • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • Thyroid Gland Carcinoma • Uterine Cancer • CD4 • MSI

WEE1 inhibitors synergise with mRNA translation defects via activation of the kinase GCN2. (PubMed, Nat Commun) - "Using a pooled CRISPRi screen, we identify GSPT1 and ALKBH8 as factors whose depletion confer hypersensitivity to the WEE1 inhibitor, AZD1775...This dual mechanism highlights opportunities for combination therapies, such as pairing WEE1 inhibitors with agents targeting the mRNA translation machinery. This study also underscores the need for more precise WEE1 targeting strategies to mitigate off-target effects, with implications for optimising the therapeutic potential of WEE1 inhibitors."

Journal • Immunology • Oncology • Targeted Protein Degradation • GSPT1

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

Development of a prognostic risk model for predicting biochemical recurrence-free survival in patients with prostate cancer based on lysine acetylation. (PubMed, Transl Androl Urol) - "Drugs such as cisplatin, MK-1775, and ulixertinib were identified as potential therapeutic agents for PCa. Five BCR-free-related prognostic genes were identified as potential therapeutic targets. Additionally, a BCR-free-related prognostic risk model was developed, offering a robust tool for predicting BCR-free survival in patients with PCa."

Journal • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • PLS3

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