Wee1

Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe (S. pombe). Wee1 has a molecular mass of 96 kDa and is a key regulator of cell cycle progression. It influences cell size by inhibiting the entry into mitosis, through inhibiting Cdk1. Wee1 has homologues in many other organisms, including mammals.

Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe (S. pombe). Wee1 has a molecular mass of 96 kDa and is a key regulator of cell cycle progression. It influences cell size by inhibiting the entry into mitosis, through inhibiting Cdk1. Wee1 has homologues in many other organisms, including mammals. ===Wee1 expression in tumors=== While multiple studies have examined the relationship between Wee1 expression and tumors, there is not a strong consensus on whether Wee1 acts as an oncogene or a tumor suppressor in cancer tissues. In some cases, studies have reported an observed overexpression of Wee1 in solid tumors / cancers like glioblastoma, hepatocellular carcinoma, melanoma, and more, as well as an association between elevated Wee1 expression and negative prognostic factors such as chemotherapy / radiotherapy resistance or other proliferation biomarkers; there are also accounts on an increased prevalence of upregulated Wee1 in instances there is also p53 loss of function. However, there are other reports which show occurrences of Wee1 downregulation (or a complete lack thereof) in cancer tissues such as non-small cell lung cancer (NSCLC), colon cancer, etc. Moreover, in certain cancers like breast cancer, there are conflicting / controversial reports. Taken together, this discussion may signal that the application and manipulation of Wee1 will likely be situation-dependent. Wee1 is very rarely mutated in cancer patients, with mutations seen at an overall frequency of around 1.2%. There is little data on how mutations affect tumor progression. ===Wee1 inhibitors=== Wee1 inhibition has been a growing therapeutic area of interest. Contrary to perhaps the typical rationale behind using inhibitor drugs to trigger cell cycle arrest, Wee1 inhibitors instead disrupt the S / G2 checkpoints to prematurely induce mitosis in cells; this mechanism thus promotes a phenomenon called "mitotic catastrophe" – increased DNA damage (insufficient repair or new events such as double-stranded breaks) that ultimately lead to apoptosis. At the cellular level, inhibiting Wee1 significantly reduces the presence of Tyr15, which consequently allows for Cdk1 kinase activity to build up and trigger entry into mitosis. ===Clinical development=== To date, there have not been many Wee1 inhibitors developed and at the clinical stage. Adavosertib (AZD1775, MK1755), developed by AstraZeneca, is a small molecule Wee1 inhibitor, and was the first of its kind to reach clinical trials. Although in 2022, the company itself removed the drug from its pipeline, multiple trials testing adavosertib as both a monotherapy or in combination were conducted. Results from randomized phase II trial FOCUS4-C demonstrated an around 2 month progression-free survival (PFS) improvement in those treated with adavosertib alone (versus the active monitoring control group); meanwhile, another trial evaluating the efficacy of adavosertib in both patients with solid tumors and clear cell renal cell carcinoma observed no objective responses (with stable disease as the best response in 10/18 enrolled patients). Other studies examining the effect of adavosertib in combination with other treatments (chemotherapy, radiotherapy, etc.) saw varying levels of impact, with the most promising data coming from trials for gynecological cancer patients. In one phase II trial using the Wee1 inhibitor in combination with carboplatin (a chemotherapy drug) in p53-mutated ovarian cancer patients, an overall response rate of 41% and median PFS of 5.6 months was observed; another combining gemcitabine (also a chemotherapy drug) and adavosertib in recurrent ovarian cancer patients reported a significant improvement in PFS (4.6 months in the treatment group vs. 3.0 months in the placebo group). It seems that a major contributor to the halt / limited continued development of adavosertib is its toxicity; several of the aforementioned studies cited patients experiencing Grade 3+ adverse events including anemia, gastrointestinal toxicities, neutropenia, thrombocytopenia, and more. Five other Wee1 inhibitors (ZN-c3, Debio-0123, SY-4835, ACR-2316, and IMP7086) are still actively under clinical evaluation. Phase I data for ZN-c3 (azenosertib, developed by Zentalis Therapeutics) shows early signs of clinical activity (2 partial responses and 5 stable disease out of 16 dosed patients) and tolerability; however, several azenosertib trials were temporarily placed on clinical hold by the FDA between June and September 2024 after two patient deaths occurred.

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