P1, N=115, Recruiting, Debiopharm International SA | Trial completion date: Jun 2025 --> Apr 2027

We employ genome-wide CRISPR-Cas9 screening for six drugs, and mediator complex, apoptosis, and erythroid-lineage-related genes are identified as key resistance hits for TKIs, whereas the Wee1 inhibitor AZD1775 and mepacrine exhibit distinct resistance profiles. KCTD5, a consistent TKI-resistance-conferring gene, is found to mediate TKI-induced BCR::ABL1 ubiquitination. In summary, we delineate potential mechanisms for primary TKI resistance and non-BCR::ABL1-targeting drugs, offering insights for optimizing CML treatment.

P2, N=25, Not yet recruiting, Joyce Liu, MD

P1, N=48, Not yet recruiting, National Cancer Institute (NCI)

P1, N=38, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2026

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P1/2, N=78, Not yet recruiting, Filipa Lynce, MD

The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.

We next highlight current chemotherapy strategies, including a combination of the FDA-approved drugs vincristine, actinomycin D, and cyclophosphamide (VAC); cabozantinib; bortezomib; vinorelbine; AZD 1775; and cisplatin. Lastly, we discuss chemotherapy agents that target the differentiation of tumor cells in ARMS, which include all-trans retinoic acid (ATRA) and 5-Azacytidine. Improving our understanding of the role of signaling pathways, such as TGF-β1, in the development of ARMS tumor cells differentiation will help inform more tailored drug administration in the future.

P2, N=124, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2024 --> Feb 2025

P1, N=74, Active, not recruiting, National Cancer Institute (NCI)

P1, N=155, Recruiting, Debiopharm International SA | Trial primary completion date: Jun 2025 --> Jan 2026

P1, N=10, Terminated, National Cancer Institute (NCI) | Active, not recruiting --> Terminated; Inadequate accrual rate

P1, N=40, Recruiting, Shouyao Holdings (Beijing) Co. LTD | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Nov 2023 --> Jun 2024

P1/2, N=120, Recruiting, Debiopharm International SA | N=89 --> 120 | Trial completion date: Mar 2028 --> Sep 2028 | Trial primary completion date: Jan 2025 --> Sep 2028

P1, N=79, Not yet recruiting, Aprea Therapeutics

Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.

P2, N=42, Completed, H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting --> Completed

P1, N=56, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

Furthermore, in vivo assessments demonstrated substantial tumor growth suppression due to WEE1 inhibitors. WEE1 inhibitors initiated an innate immune response in endometrial cancer, exhibiting considerable anti-tumoral effects, which was promising for postoperative treatment of endometrial cancer, especially recurrent endometrial cancer patients.

This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8+ T cells in TME.

P2, N=49, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | N=80 --> 49 | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=54, Recruiting, Debiopharm International SA

In this study, we reported that high CHK1 and WEE1 expression is associated with poor outcome in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy...These data emphasize that MM cell adaptation to replicative stress through Wee1 and Chk1 upregulation may decrease the activation of the cell-intrinsic innate immune response. Our study suggests that association of Chk1 and Wee1 inhibitors may represent a promising therapeutic approach in high-risk MM patients characterized by high CHK1 and WEE1 expression.

P2, N=34, Recruiting, Brandon Huffman | Not yet recruiting --> Recruiting

Despite the defect in the replication stress response, FBH1-deficiency sensitizes cells to WEE1 inhibition by increasing mitotic catastrophe. We propose loss of FBH1 is resulting in replication-associated damage that requires the WEE1-dependent G2 checkpoint for repair.

As a result, recent efforts have been made to explore predictive biomarkers and smart combination schedules to alleviate dose-limiting effects. In this review, we focused on the exploration of therapeutic biomarkers, as well as schedules of combination utilizing WEE1 inhibitors and canonical anticancer drugs, according to the latest preclinical and clinical studies, indicating that the optimal application of WEE1 inhibitors will likely be as part of dose-reducing combination and be tailored to specific patient populations.

Through the utilization of western blotting analyses, targeted inhibitors, and ectopic overexpression, we propose that the downregulation of Wee1, CHK1, RNR, and c-Myc are the potential mechanisms. Our data support the development of ADA in combination with CUDC-907 for the treatment of AML.

We further showed here that the combination of E2F8 knockdown with MK-1775, an inhibitor of WEE1 being evaluated in clinical trials, synergistically suppressed proliferation and promoted apoptosis of LUAD cells in vitro and in vivo. Thus, this study reveals a novel role of E2F8 as a proto-oncogenic transcription activator by activating RRM2 expression in LUAD, and targeting both the transcription and degradation mechanisms of RRM2 could produce a synergistic inhibitory effect for LUAD treatment in addition to conventional inhibition of RR enzyme activity.

P2, N=130, Recruiting, K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Trial completion date: Dec 2023 --> May 2025 | Trial primary completion date: Dec 2022 --> Nov 2024

Promising drugs inhibiting kinases like Wee1 (Adavosertib), Wee1+Myt1 (PD166285), ATR (AZD6738) and Chk1 (UCN-01) have been developed, but clinical data has shown variable efficacy for them with poorly understood mechanisms of resistance. Elevated Myt1 levels also conferred resistance to inhibitors of ATR or Chk1 inhibitor. Our data supports that Myt1 overexpression is a common mechanism by which cancer cells can acquire resistance to a variety of drugs entering the clinic that aim to induce mitotic catastrophe by abrogating the G2/M checkpoint.

P1/2, N=84, Active, not recruiting, K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Recruiting --> Active, not recruiting

P1, N=130, Recruiting, Debiopharm International SA | Trial completion date: Dec 2023 --> Jun 2027 | Trial primary completion date: Aug 2023 --> Jun 2025

P2, N=104, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

We demonstrate the synergistic effects of WEE1 inhibitor (MK1775/AZD1775) and PKMYT1 inhibitor (RP6306) in a panel of TNBC and ER+ve breast cancer cells with acquired palbociclib resistance (PalboR). Overall, this study highlights the potential therapeutic benefits of dual inhibition of WEE1 and PKMYT1 in overcoming CDK4/6 inhibitor resistance in TNBC and ER+ve breast cancer patients. These findings provide a rationale for future clinical trials aimed at exploring the clinical utility of this combination therapy.

P1, N=33, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

P1, N=43, Not yet recruiting, The Netherlands Cancer Institute

There were 35 evaluable patients on each arm. Patients received a median of 4 prior therapies (range 1-11), including olaparib (41%). Median PFS was 5.5 months (95% CI, 3.9-6.9) from A and 6.8 months (95% CI, 4.3-8.3) from A/O.

CHRNA6 may be associated with immune infiltration in LUSC and affects patient prognosis and immunotherapeutic response by regulating immune cells and immune pathways. In addition, adavosertib may be a potential drug for the treatment of LUSC.

Herein, a glutathione (GSH)-responsive nanoparticle (NP2) loaded with cisplatin prodrug (Pt (IV)) and WEE1 inhibitor (MK1775) was designed. As innate and adaptive immune responses were stimulated, the immunosuppressive microenvironment was modified, and the "immune cold tumor" was transformed into an "immune hot tumor". In addition, NP2 could upregulate PD-L1 expression in tumor cells, thereby increasing the response rate of PD-L1 monoclonal antibody (?PD-L1) and eliciting long-term immune responses in both primary and metastatic tumors.

Checkpoint abrogation, by the Wee1 kinase inhibitor adavosertib, induced glioblastoma cell lines and primary cells, DNA-damaged by UNC0379, to progress to mitosis where they died by mitotic catastrophe. Finally, UNC0379 and adavosertib synergized in restraining glioblastoma growth in a murine xenograft model, providing a strong rationale to further explore this novel pharmacological approach for adjuvant glioblastoma treatment.