adavosertib (AZD1775)

P1, N=117, Active, not recruiting, AstraZeneca | Trial completion date: Jun 2024 --> Mar 2025

MK-1775 enhances the cytotoxic effects of gemcitabine and pemetrexed in NSCLC cell lines and effectively inhibits tumor growth in vivo. These findings suggest that Wee1 inhibition by MK-1775, combined with chemotherapy, represents a promising therapeutic strategy for NSCLC treatment.

This study explored Wee1 expression in ACC and its regulation by FLNA, the effects of Wee1 inhibitor AZD1775, and the impact of FLNA on its efficacy in ACC cell lines and primary cells...In conclusion, we demonstrated that FLNA regulates Wee1 expression by promoting its degradation, suggesting that low FLNA typical of ACC leads to increased Wee1 with consequent cancer cells growth. It proposes Wee1 inhibition as a new potential therapeutic approach for ACC, particularly for those lacking FLNA.

P2, N=104, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1, N=13, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

Therefore, we investigated the effect of inhibiting WEE1 on delaying the development of resistance to palbociclib and fulvestrant. Furthermore, we developed a mathematical model that can simulate cell proliferation under monotherapy, combination or 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.

RNA sequencing and immunohistochemistry analyses of mouse tumors revealed that treatment with the WEE1 inhibitor activated tumor immunity and suppressed stromal reactions. These results demonstrate the potential antitumor effects of WEE1 inhibitors in CRC, particularly in patients with p53 mutations.

This study provides pre-clinical evidence that AKT inhibitors combined with PI3K inhibitors, cisplatin, or vincristine exhibit additive/synergistic anti-MB activity, and lower doses could be used. The latter also applied to one MB line grown as spheroids, further supporting their future potential use.

Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin...Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D (Act...Altogether, our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.

Our preclinical study identifies WEE1-mediated replication stress tolerance as molecular vulnerability in FUS::DDIT3-driven MLS tumorigenesis that could represent a novel target for therapeutic intervention.

The WEE1 inhibitor MK-1775 effectively inhibited the proliferation and migration of LGG cell lines, which were more sensitive to WEE1 inhibition...Notably, significant differences were observed in the role of WEE1 between LGG and GBM. Further investigation into WEE1 inhibition, either in combination with DNA methyltransferase inhibition or immunotherapy, is warranted in the context of LGG.

P2, N=60, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Aug 2024 --> Aug 2025

Subsequent evaluation of the combination therapy involving Adavosertib and DSF-Cu reveals reduced cell viability along with smaller tumor volumes and lighter tumor weights observed both in p53-deficient cells as well as in xenograft models while correlating with solute carrier family 7-member 11 (SLC7A11)/glutathione-regulated ferroptosis pathway activation. In conclusion, our findings elucidate the molecular interplay between p53 and WEE1 and unveil a novel synergistic therapeutic strategy for treating p53-deficient NSCLC.

In BALTIC, all combination regimens demonstrated tolerable safety profiles, but antitumor activity was limited in refractory/resistant ES-SCLC. Among patients treated with durvalumab plus tremelimumab, an association of on-treatment reduction in ctDNA with longer OS suggests the potential use of ctDNA as a surrogate of treatment response, warranting further investigation.

Historically, treatment options for PROC were limited with a poor prognosis and non-platinum single agent plus bevacizumab has been the mainstay of treatment...WEE1 inhibitors, such as adavosertib, function by inhibiting the WEE1 kinase activity, leading to premature entry of a cell into mitosis phase and thus increased DNA damage...Biomarker testing such as analysis of the expression level of folate receptor alpha or mutation in TP53 may be applicable for identifying patients who are more likely to respond to the specific therapy, enabling a more personalized treatment approach. This overview summarizes key clinical findings on the efficacy and safety of theses novel biomarker-driven therapeutic approaches.

These findings emphasize the important role of lipid metabolism in shaping the complex tumor microenvironment. By manipulating the intricate intricacies of lipid metabolism within the tumor microenvironment, we can uncover and develop promising strategies to sensitize immunotherapy, potentially revolutionizing cancer treatment approaches.

Our data indicate that, rather than acting via abrogation of cell cycle checkpoints, ATR, CHK1 and WEE1 inhibitors cause an HRD phenotype and hence "induced synthetic lethality" with PARPi.

Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies though prolonged stable disease was observed in a subset of pts. Combination approaches may yield greater depth of tumor response.

Taken together, our findings provide experimental evidence for the future use of sorafenib in combination with RP-6306 or adavosertib for the treatment of HCC.

In Atm-/-nu-/-lymphomas, we discovered nucleotide biosynthesis as a MYCdependent cellular vulnerability that can be targeted through the synergistic nucleotidedepleting actions of mycophenolate mofetil (MMF) and the WEE1 inhibitor, adavosertib (AZD1775). Validation in cell line models of human DLBCL confirmed the broad applicability of nucleotide depletion as a therapeutic strategy for MYC-driven DLBCL independent of ATM mutation status. Our findings extend current understanding of lymphomagenic mechanisms underpinning ATM loss and highlight nucleotide metabolism as a targetable therapeutic vulnerability in MYC-driven DLBCL.

Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell cycle and cell fate regulation, and a rationale for sequential administration of WEE1 inhibitors with low toxicity inhibitors of pre-BCR signaling or metabolism.

Curcumin alone led to dose-dependent responses and when combined with BYL719, positive effects were revealed, as they were when it was combined with MK-1775 or PD-0332991, suggesting a potential use of some of these combinations for HPV+ OPSCC.

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.

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

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)

P2, N=200, Active, not recruiting, Canadian Cancer Trials Group | Recruiting --> Active, not recruiting | N=600 --> 200

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

P2, N=600, Recruiting, Canadian Cancer Trials Group | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

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

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

P2, N=72, Completed, AstraZeneca | Active, not recruiting --> Completed

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.

P1, N=156, Active, not recruiting, AstraZeneca | Phase classification: P1b --> P1 | Trial completion date: Sep 2023 --> Jun 2024

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.