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

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.

Molecular and therapeutic advancements in Capicua (CIC)-rearranged sarcoma

“…In order to prevent the accumulation of DNA damage in S phase and to subsequently prevent premature mitotic entry, CIC::DUX4 sarcomas depend on the G2/M checkpoint kinase WEE1 to delay mitotic entry and to ensure proper DNA repair and integrity prior to mitosis. Thus, WEE1 kinase inhibition with adavosertib has been shown to induce tumor regression in CIC::DUX4 tumor xenograft models (Ponce et al, 2022). These preclinical studies provide rationale to develop CDK2 and WEE1 inhibitor-based clinical trials for CIC:: DUX4 patients.…”

“…Consistent with this, we and others have observed that global CIC::DUX4 binding overlaps with H3K27ac marks in patient derived CIC::DUX4 cell lines, again suggesting that p300/CBP may in part confer activating capacity (Thomas et al, 2023;Bakaric et al, 2024). Collectively, CIC co-opts the activating capacity of the p300/CBP associated transcription factor, DUX4, to upregulate key target genes including PEA3 family members, cell cycle genes such as CCND2 and CCNE1, and negative MAPK regulators including DUSP4 and DUSP6 that drive malignant phenotypes in aggressive undifferentiated round cell sarcomas (Kawamura-Saito et al, 2006;Yoshimoto et al, 2017;Okimoto et al, 2019;Ponce et al, 2022). Collectively, these structurefunction studies reveal that CIC::DUX4 largely retains CIC DNAbinding specificity while transforming its native repressor function (SIN3-HDAC and SWI/SNF) into a potent oncogene in part through DUX4 mediated p300/CBP recruitment.…”

“…Recent studies have focused on understanding the mechanistic underpinnings of the CIC:: DUX4 fusion oncoprotein, illuminating potential druggable targets (Table 2). Preclinical studies identified CIC::DUX4 to molecularly depend on cell cycle mediators CCNE1 and WEE1 (Okimoto et al, 2019;Ponce et al, 2022) with CCNE1 being established as a direct transcriptional target of CIC::DUX4 that drives tumor growth and survival through an acquired dependence on CCNE/CDK2 complex. Hyperactivation of the CCNE/ CDK2 complex compromises the G1/S transition and confers sensitivity to CDK2 inhibitors in a relatively fusion specific manner (Okimoto et al, 2019).…”