Targeting WEE1 Kinase for Breast Cancer Therapeutics: An Update

Abstract

WEE1 kinase is a crucial cell cycle regulatory protein that controls the timing of mitotic entry. WEE1, via inhibition of Cyclin-dependent Kinase 1 (CDK1) and Cyclin-dependent Kinase 2 (CDK2), governs the G2-M checkpoint by inhibiting entry into mitosis. The state of balance between WEE family kinases and CDC25C phosphatases restricts CDK1/CycB activity. The WEE kinase family consists of WEE1, PKMYT1, and WEE2 (WEE1B). WEE1 and PKMYT1 regulate entry into mitosis during cell cycle progression, whereas WEE2 governs cell cycle progression during meiosis. Recent studies have identified WEE1 as a potential therapeutic target in several cancers, including therapy-resistant triple-negative breast cancer. 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. Preclinical studies show WEE1 inhibitors induce MHC class 1 antigens and STING when given as combination therapies, suggesting potential additional therapeutic opportunities. 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.

Keywords: DNA damage/repair; G2/M checkpoint; WEE1 inhibitors; WEE1 kinase; breast cancer; cell cycle regulation; chemotherapy resistance; clinical trial; cyclin-dependent kinases; mitotic entry.

Figure 1

(A) Graphical timeline summarizing the evolution of WEE1 kinase as a therapeutic target in cancer [29,30,31,32]. (B) Schematic representation of the role of WEE1 in regulating intra-S checkpoint, G2/M checkpoint, and mitosis exit.

Figure 2

The figure describes the prognosis and the prevalence (% incidence) of the five phenotypic breast cancer subtypes. The size of the cancer cluster denotes the proportional contribution to cancer mortality for that subtype. Expression of key receptors in the progression of breast cancer and the proliferative potential (Ki67 positivity) of each subtype are also shown.

Figure 3

Kaplan–Meier plot from the TCGA BRCA database showing significant lower overall survival in WEE1-overexpressed breast cancer patients in comparison to patients with low WEE1 expression.

Figure 4

(A) Box plot showing comparison of WEE1 expression in normal breast tissue versus and breast cancer tissue samples (TCGA BRCA). (B,C) Box plots representing the gene and protein expression, respectively, of WEE1 in breast cancer patients based on the major subclasses. The analysis was conducted in TCGA BRCA cancer transcriptome data using the UALCAN database.

Figure 5

Schematic illustration of WEE1 inhibitors investigated in combination therapies during preclinical studies.

Figure 6

Schematic representation summarizing the predictors of response to WEE1 inhibitors.