Targeting WEE1 Kinase in Cancer

WEE1 kinase is the gatekeeper of the G2–M cell-cycle checkpoint that allows DNA repair before mitotic entry. WEE1 is highly expressed and active in several cancer types that depend on a functional G2–M checkpoint for DNA repair. Targeting WEE1 for inhibition and compromising the G2–M checkpoint presents an opportunity to potentiate chemotherapy. The potent WEE1 inhibitor AZD1775 has advanced to clinical trials in combination with DNA-damaging therapies in various cancer types. Although AZD1775 has advanced to clinical trials and is well tolerated, studies will be necessary to determine the potential toxicities associated with this compound and with WEE1 inhibition. There are few WEE1 inhibitors and there is scope to improve WEE1 inhibitor selectivity and the properties of the inhibitors to permit targeting of specific cancer types. WEE1 kinase plays a crucial role in the G2–M cell-cycle checkpoint arrest for DNA repair before mitotic entry. Normal cells repair damaged DNA during G1 arrest; however, cancer cells often have a deficient G1–S checkpoint and depend on a functional G2–M checkpoint for DNA repair. WEE1 is expressed at high levels in various cancer types including breast cancers, leukemia, melanoma, and adult and pediatric brain tumors. Many of these cancers are treated with DNA-damaging agents; therefore, targeting WEE1 for inhibition and compromising the G2–M checkpoint presents an opportunity to potentiate therapy. In this review we summarize the current WEE1 inhibitors, the potential for further inhibitor development, and the challenges in the clinic for the WEE1 inhibitor strategy. WEE1 kinase plays a crucial role in the G2–M cell-cycle checkpoint arrest for DNA repair before mitotic entry. Normal cells repair damaged DNA during G1 arrest; however, cancer cells often have a deficient G1–S checkpoint and depend on a functional G2–M checkpoint for DNA repair. WEE1 is expressed at high levels in various cancer types including breast cancers, leukemia, melanoma, and adult and pediatric brain tumors. Many of these cancers are treated with DNA-damaging agents; therefore, targeting WEE1 for inhibition and compromising the G2–M checkpoint presents an opportunity to potentiate therapy. In this review we summarize the current WEE1 inhibitors, the potential for further inhibitor development, and the challenges in the clinic for the WEE1 inhibitor strategy.