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bioRxiv · 10.1101/2021.06.21.448439

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

Ponce, R. K.·Thomas, N. J.·Bui, N. Q.·Kondo, T.·Okimoto, R. A.
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Abstract

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, conferring a potential survival 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 an adaptive survival mechanism. Specifically, CIC-DUX4 sarcomas depend on WEE1 activity to limit DNA damage and unscheduled mitotic entry. Consequently, genetic or pharmacologic WEE1 inhibition in vitro and in vivo leads to rapid DNA damage-associated apoptotic induction of patient-derived CIC-DUX4 sarcomas. Thus, we identify WEE1 as an actionable therapeutic vulnerability in CIC-DUX4 sarcomas.

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Ponce, R. K., Thomas, N. J., Bui, N. Q., Kondo, T., Okimoto, R. A.. 2021-06-22. WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma.. https://doi.org/10.1101/2021.06.21.448439

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