WEE1 INHIBITION AS ANTICANCER STRATEGY: FIRST ADVANCES

WEE1 is a key regulator of the G2/M checkpoint and it is commonly deregulated in cancer. Several RNA interference screens have highlighted the potential therapeutic role of targeting WEE1 in cancer. In preclinical models, WEE1 inhibitors have been shown to sensitize cell lines from a wide range of tumors to radiotherapy or chemotherapy. WEE1 inhibition abrogates the G2/M arrest induced by radiation or chemotherapy; hence, cells with unrepaired DNA damage enter into mitosis, leading to cell death. In some tumor cell lines, loss of functional p53 is required to achieve synergy between a WEE1 inhibitor (PD-166285 or MK-1775) and a DNA-damaging agent; in others, such as glioblastoma or osteosarcoma cell lines, activity is independent of p53 status. Novel promising targeted agent combinations, such as MK1775 and serine/threonine-protein kinase Chk1 inhibitors, are currently under preclinical evaluation. The WEE1 inhibitor MK-1775 is presently being evaluated in several clinical trials alone and in combination with chemotherapy and or radiotherapy. Data reported to date from the early-phase clinical studies suggest that MK-1775 is well tolerated and that combination studies are feasible. Ongoing trials will provide further data on safety and include biomarker studies, which may help to identify predictive biomarker signatures to better select patients who may benefit from this approach.