WEE1 Kinase Targeting Combined with DNA-Damaging Cancer Therapy Catalyzes Mitotic Catastrophe

Abstract

WEE1 kinase is a key molecule in maintaining G 2 -cell-cycle checkpoint arrest for premitotic DNA repair. Whereas normal cells repair damaged DNA during G 1 -arrest, cancer cells often have a deficient G 1 -arrest and largely depend on G 2 -arrest. The molecular switch for the G 2 -M transition is held by WEE1 and is pushed forward by CDC25. WEE1 is overexpressed in various cancer types, including glioblastoma and breast cancer. Preclinical studies with cancer cell lines and animal models showed decreased cancer cell viability, reduced tumor burden, and improved survival after WEE1 inhibition by siRNA or small molecule inhibitors, which is enhanced by combination with conventional DNAdamaging therapy, such as radiotherapy and/or cytostatics. Mitotic catastrophe results from premature entry into mitosis with unrepaired lethal DNA damage. As such, cancer cells become sensitized to conventional therapy by WEE1 inhibition, in particular those with insufficient G 1 -arrest due to deficient p53 signaling, like glioblastoma cells. One WEE1 inhibitor has now reached clinical phase I studies. Dose-limiting toxicity consisted of hematologic events, nausea and/or vomiting, and fatigue. The combination of DNA-damaging cancer therapy with WEE1 inhibition seems to be a rational approach to push cancer cells in mitotic catastrophe. Its safety and efficacy are being evaluated in clinical studies.

A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity

“…Inhibition of Wee1 potentiates DNA-damaging chemotherapeutics and radiotherapy and has cytotoxic effects as a single agent (19)(20)(21)(22). The consensus view is that Wee1 inhibition facilitates tumor cell killing through G 2 /M checkpoint inactivation, which would catalyze mitotic catastrophe (23)(24)(25). As expected, Wee1 inhibition is synergistic with DNA-damaging agents, specifically in TP53-mutant cancer cell lines (3).…”

Cytokinetic effects of Wee1 disruption in pancreatic cancer

“…Since the G2 phase of the cell cycle provides a pause during which post-replication errors and breaks are corrected, its premature termination by Wee1 inhibition might promote the mitotic death of cells failing to complete repair. 12,25,35 This could be particularly relevant to pancreatic cancers, given their high degree of genomic instability. However, there was no significant single agent activity in our PDX models, which is consistent with the low response rate of MK-1775 (AZD1775) in human clinical trials.…”

Science in Focus: Combining Radiotherapy with Inhibitors of the DNA Damage Response

“…Many of the functions of ATR are mediated through phosphorylation and activation of Chk1, and while Chk1 inhibitors have exhibited promising radiosensitising effects in preclinical studies, toxicity issues have hampered their clinical development. More recently, inhibition of Wee1, another kinase that promotes G2/M checkpoint activation in response to radiation, has emerged as a potential therapeutic strategy [17]. As with ATM inhibitors, a number of studies have indicated that the effects of ATR or Wee1 inhibitors are more pronounced in p53 defective contexts [18,19].…”