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

Preclinical drug screen identifies WEE1 inhibitor and vinca alkaloid as a combination treatment concept for Li-Fraumeni syndrome medulloblastoma. (PubMed, iScience) - "The combination of WEE1 inhibitor adavosertib and vinca alkaloid vincristine demonstrated the highest activity, which was validated in TP53mut SHH-MB patient-derived organoids. Despite the drugs' limited efficacy in the in vivo PDX model, WEE1 knockdown led to significant growth reduction in in vitro and in vivo TP53mut SHH-MB models. Our findings identify WEE1 as a promising target in LFS SHH-MB, suggesting its inhibition combined with vincristine treatment as a potential chemotherapeutic strategy."

Journal • Preclinical • Brain Cancer • Medulloblastoma • Metabolic Disorders • Oncology • Solid Tumor • TP53

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

Pharmacological WEE1 inhibition as a strategy to overcome cisplatin resistance in non-seminoma testicular cancer: insights from preclinical models. (PubMed, Sci Rep) - No abstract available

Journal • Preclinical • Genito-urinary Cancer • Germ Cell Tumors • Oncology • Solid Tumor • Testicular Cancer

Transcription termination counteracts DNA damage after WEE1 inhibition. (PubMed, Nucleic Acids Res) - "Elevated expression of CPSF73 is associated with aggressive disease in prostate cancer patients, and combining JTE-607 with adavosertib synergistically reduced prostate cancer cell survival. Our findings suggest that transcription termination helps prevent toxic conflicts between transcription and replication following increased replication initiation caused by WEE1 inhibition."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CDC73 • DDX5 • PAF1

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

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

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: Dec 2026 ➔ Jul 2027 | Trial primary completion date: Dec 2025 ➔ Jul 2026

P53mut • Trial completion date • Trial primary completion date • Carcinosarcoma • Endometrial Serous Adenocarcinoma • Oncology • Sarcoma • Solid Tumor • Uterine Cancer

A New Class of Multitargeting PtIV Anticancer Agents: Prodrugs That Release PtII Drugs and Bioactive Moieties Tethered to PtIV via a Tertiary Amine. (PubMed, J Med Chem) - "Herein, we describe the general approach for design and synthesis of PtIV complexes conjugated to organic drugs (brigatinib, osimertinib, adavosertib, and irinotecan) via their tertiary amines. The PtIV prodrugs conjugated to tyrosine kinase inhibitors (TKIs) showed potent anticancer activity in 2D and 3D cancer models by combining the modes of action of platinum and TKi. They inhibited in vivo tumor growth in an LLC model better than brigatinib, osimertinib, and cisplatin with significantly lower body weight loss."

Journal • Oncology

EFFORT: Adavosertib With or Without Olaparib in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer (clinicaltrials.gov) - P2 | N=96 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • BRCA • HRD

Personalized drug screening and risk assessment in patient-derived gastroenteropancreatic neuroendocrine neoplasms. (PubMed, J Clin Endocrinol Metab) - "We provide novel data on the efficacy of putative and established therapies in patient-derived GEP-NEN primary cultures. Our standardized platform for personalized drug screening and risk assessment in GEP-NEN primary cultures enables prediction of individual tumor treatment response in this orphan disease."

Journal • Endocrine Cancer • Gastrointestinal Neuroendocrine Carcinoma • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • CDK4

LncRNA Wee1-AS coordinates oxidative fatty acid metabolism through the activation of mitochondrial CDK1/CYCLIN B1. (PubMed, Signal Transduct Target Ther) - "Consistently, knockdown of Wee1-AS led to lipid accumulation and mitochondrial dysfunction, both of which were reversed by adavosertib treatment in hepatocytes, indicating a functional interplay between Wee1-AS and WEE1 in regulating fatty acid oxidation. Furthermore, we identified a human homolog, LNC106435.1, which improved mitochondrial function, suggesting that the modulation of LNC106435.1 may have potential therapeutic implications for managing MASLD."

Journal • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Targeted Protein Degradation • CCNB1 • CDK1 • WEE1

Targeting the DNA damage response prevents regrowth of colorectal peritoneal metastasis-derived organoids following treatment with mitomycin C. (PubMed, Br J Cancer) - "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."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CHEK1

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

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 • Platinum resistant • 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

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