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

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

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

CDK2 activation mediates response of acute myeloid leukemia to CHK1, ATR and WEE1 inhibitors (AACR 2025) - "Here we have comprehensively characterized the processes that occur between the interruption of replication checkpoints and leukemic cell death in these sensitive cells versus cells selected for RCM resistance. Using the CHK1 inhibitors MK8776 and prexasertib, ATR inhibitors berzosertib and ceralasertib, and WEE1 inhibitor adavosertib as paradigm drugs, we examined signaling in two AML cell lines, U937 and THP.1, that were selected for CHK1 inhibitor resistance, examined cross-resistance patterns, and assessed the biochemical basis for leukemic cell death. Our findings reveals critical new insights into the factors that influence the response to CHK1 inhibitors in AML. Importantly, we found no evidence of cross-resistance to inhibitors of other replication checkpoint proteins, enabling alternative options."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CDC25A • CDK2 • CHEK1 • GNRP • TNFA • TP53

INK4A/B as predictive biomarkers for enhanced efficacy of dual WEE1 and PKMYT1 inhibition in CDK4/6 inhibitor-resistant breast cancer (AACR 2025) - "This study aimed to identify predictive biomarkers of response to WEE1/PKMYT1 dual inhibition while maintaining manageable toxicity. Evaluating WEE1 inhibitors (adavosertib or azenosertib) in combination with the PKMYT1 inhibitor (lunresertib) across CDK4/6i-R and TNBC models, including patient-derived xenografts (PDXs) and organoids, demonstrated significant tumor suppression, with the novel dual WEE1/PKMYT1 inhibitor SGR-3515 showing comparable efficacy... Dual inhibition of WEE1 and PKMYT1 presents a compelling therapeutic strategy for CDK4/6i-R breast cancer and TNBC. Elevated baseline levels of INK4A and INK4B are strongly associated with enhanced treatment responses, highlighting their potential as predictive biomarkers for selecting patients likely to benefit from WEE1/PKMYT1 dual inhibition therapy."

Biomarker • Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • CDKN2A • CDKN2B • ER • HER-2 • PKMYT1

Cyclin E1 overexpression as a predictive biomarker for PLK1 and WEE1 inhibitor efficacy in ovarian cancer (AACR 2025) - "Twelve ovarian cancer cell lines (5 high-grade serous [HGSOC], 5 clear cell [CCOC], and 2 endometrioid [EOC] ovarian carcinomas) were treated with the PLK1 inhibitor volasertib and the WEE1 inhibitor adavosertib to evaluate drug sensitivity, cell cycle effects, and apoptosis in vitro, as well as tumor growth in vivo. Both inhibitors induced cleaved PARP and γH2AX in high Cyclin E1-expressing tumors but not in low-expression models. Cyclin E1 overexpression, regardless of TP53 status, may serve as a predictive biomarker for the efficacy of these inhibitors, thereby offering potential personalized treatment strategies for ovarian cancer."

Biomarker • Clinical • Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • PLK1 • TP53

WEE1 as a therapeutic target in TP53 and ARID1A concurrent mutant colorectal cancers (AACR 2025) - P2 | "Notably, ARID1A knockout sensitizes TP53-mutant, but not TP53-wildtype CRC cell lines, to WEE1 inhibitor MK-1775 or ZN-c3...These studies paralleled a phase 1b/2 clinical trial with SC0191 (a novel WEE1 inhibitor) based combination therapy in a cohort of late-line metastatic CRC patients (NCT06363552)...In conclusion, our research showed that targeting WEE1 is effective in TP53 and ARID1A mutant colorectal cancers. This therapeutic strategy is being tested in a phase 2 study for mCRC patients."

Colorectal Cancer • Oncology • Solid Tumor • ARID1A • TP53 • WEE1

BISCAY: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Jan 2026

Biomarker • Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CCNE1 • CDKN2A • HRD • MYCL • MYCN • RB1

Machine Learning-based Gene Biomarker Identification for Improving Prognosis and Therapy in Hepatocellular Carcinoma. (PubMed, Curr Med Chem) - "Our study demonstrates a well-rounded approach by integrating gene expression, machine learning, tumor microenvironment analysis, and drug sensitivity profiling. HPRI may serve as a promising predictor for guiding prognosis and personalized treatment in HCC."

Biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • PABPC1 • PLOD2 • PPARGC1A

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

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

Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids. (PubMed, J Med Chem) - "A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (1), many of which were more selective for WEE1 over an undesirable off-target of 1, the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from TP53-mutated colorectal cancer (CRC) peritoneal metastases, 34 (IC50 value of 62 nM) exhibited stronger efficacy than 1 (IC50 value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC50 value of 127 nM). Against primary CRC PDOs with TP53-WT, 34 significantly enhanced DNA damage, replication stress and apoptosis compared to 1, as well as demonstrated high selectivity over patient-matched normal healthy colon PDOs, highlighting a potential therapeutic window for cancer treatment. Overall, this investigation provides critical insight into several potent WEE1 inhibitors that exhibited exceptional efficacy against CRC PDOs and is the first to utilize a PDO platform to assess their..."

Journal • Colorectal Cancer • Oncology • Solid Tumor • PLK1 • TP53

NCI-2014-00620: Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer (clinicaltrials.gov) - P2 | N=124 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Feb 2025 ➔ Feb 2026

Monotherapy • Platinum resistant • Trial completion date • Carcinosarcoma • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Sarcoma • Solid Tumor

WEE1 Inhibition in Cancer Therapy: Mechanisms, Synergies, Preclinical Insights, and Clinical Trials. (PubMed, Crit Rev Oncol Hematol) - "WEE1 inhibitors, especially adavosertib (AZD1775), have shown strong preclinical and clinical activity in ovarian, breast, gastrointestinal, and head and neck cancers...This review highlights key findings from preclinical and clinical studies, explores emerging biomarkers for patient stratification, and discusses strategies to overcome resistance and toxicity. By integrating current knowledge, we aim to provide insights into optimizing WEE1-targeted therapies and guiding future research to maximize their clinical impact in cancer treatment."

IO biomarker • Journal • Preclinical • Review • Gastrointestinal Disorder • Head and Neck Cancer • Oncology • Solid Tumor • CDK1 • TP53

Identification of m6A-associated autophagy genes in non-alcoholic fatty liver (APASL 2025) - "Ultimately, we found that the TF-mRNA network included FOXP1-GOPC, ATF1- RAB1A and other relationship pairs, and eight therapeutic agents such as R-406 and adavosertib were predicted based on the TBK1. The study investigated the potential molecular mechanisms of m6A related autophagy feature genes (TBK1, RAB1A, and GOPC) in NAFLD through bioinformatic analyses and animal model validation. However, it is critical to note that these findings, although consequential, demonstrate correlations rather than cause- and-effect relationships. As such, more research is required to fully elucidate the underlying mechanisms and validate the clinical relevance of these feature genes."

Hepatology • Metabolic Dysfunction-Associated Steatotic Liver Disease • ATF1 • FOXP1 • TBK1