Molecular Pathways: Targeting the Protein Kinase Wee1 in Cancer

Abstract

Wee1 is a protein kinase that regulates the G checkpoint and prevents entry into mitosis in response to DNA damage. Cyclin-dependent kinases (CDK) are a family of 14 serine/threonine protein kinases that coordinate the progression through the cell cycle. The Cdc2/cyclin B complex controls the progression from G into mitosis. There are two mechanisms by which the G checkpoint is initiated in response to DNA damage: phosphorylation of Cdc25c by CHK1 and of the Wee1 kinase, which phosphorylates Cdc2. Blockade at the G checkpoint is especially important for p53-mutant cells because these tumors mainly rely on DNA repair at the G checkpoint. AZD1775 (formerly MK-1775) is a small-molecule, pyrazol-pyrimidine derivative and potent and ATP-competitive specific inhibitor of the Wee1 kinase. Several preclinical and clinical studies demonstrated encouraging antitumor effects with manageable side effects of the combination of Wee1 inhibition and DNA-damaging agents. Promising combination schedules are being investigated at the moment, for example, combining PARP inhibition and Wee1 inhibition. Also, a weekly schedule with carboplatin and AZD1775 warrants investigation aimed at further improving the antitumor effect. .

BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

“…In addition, BRD4 may regulate distal enhancer activity in addition to promoter activity (Shi and Vakoc, 2014). Regardless, our results are consistent with the previously reported roles of WEE1 and TOPBP1 in regulating PARP inhibitor sensitivity (Geenen and Schellens, 2017; Li et al, 2014; Moudry et al, 2016). Given the potentially broad applicability of the BET inhibitor and PARP inhibitor combination in human cancers regardless of BRCA1/2 mutational status, we anticipate our findings to have far-reaching implications for developing future combinatory cancer therapeutics.…”

“…Interestingly, among the genes identified, nascent transcripts for WEE1 and TOPBP1 were significantly downregulated based on RNA-seq, and the binding of BRD4 to the promoter regions of both genes were decreased by JQ1 treatment (Figure 1C). Given the known role of WEE1 and TOPBP1 in regulating PARP inhibitor sensitivity (Geenen and Schellens, 2017; Li et al, 2014; Moudry et al, 2016), we focused our studies on these two genes. Indeed, we validated the nascent RNA-seq results by showing that mRNA levels of both WEE1 and TOPBP1 were decreased by JQ1 treatment (Figure 1D).…”

“…Given the known roles of WEE1 and TOPBP1 inhibition in sensitizing cells to PARP inhibition (Geenen and Schellens, 2017; Moudry et al, 2016), we examined whether JQ1 synergizes with the PARP inhibitor Olaparib in BRCA1/2 wild-type cells. Based on a combination index, JQ1 displayed a synergistic effect with Olaparib in BRCA1/2 wild-type OVCAR3 cells (Figure 2A–C).…”

“…Notably, combined inhibition of WEE1 and PARP sensitizes pancreatic cancer to radiotherapy, which correlates with WEE1’s role in HR. (Geenen and Schellens, 2017). …”

Downregulation of lncRNA NEAT1_2 radiosensitizes hepatocellular carcinoma cells through regulation of miR‐101‐3p/WEE1 axis

“…In addition, ectopic expression of miR-101-3p induced a notable inhibition of cell proliferation, migration, and invasion in non-small cell lung cancer cells through suppressing the PI3K/AKT signal pathway by targeting MALAT-1 (Zhang et al, 2017). WEE1, a tyrosine kinase, belongs to the Ser/Thr family of protein kinases and acts as a momentous regulator of cell cycle that can regulate cell size through inhibiting entry into mitosis (Geenen and Schellens, 2017). In the present study, we found that miR-101-3p was downregulated in HCC tissues, as well as HCC cell lines.…”