WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma

CIC-DUX4 rearrangements define an aggressive and chemotherapy-insensitive subset of undifferentiated sarcomas. The CIC-DUX4 fusion drives oncogenesis through direct transcriptional upregulation of cell cycle and DNA replication genes. Notably, CIC-DUX4–mediated CCNE1 upregulation compromises the G1/S transition to confer a dependence on the G2/M cell cycle checkpoint. Through an integrative transcriptional and kinase activity screen using patient-derived specimens, we now show that CIC-DUX4 sarcomas depend on the G2/M checkpoint regulator WEE1 as part of an adaptive survival mechanism. Specifically, CIC-DUX4 sarcomas depended on WEE1 activity to limit DNA damage and unscheduled mitotic entry. Consequently, genetic or pharmacologic WEE1 inhibition in vitro and in vivo led to rapid DNA damage–associated apoptotic induction of patient-derived CIC-DUX4 sarcomas. Thus, we identified WEE1 as a vulnerability targetable by therapeutic intervention in CIC-DUX4 sarcomas.