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

Ponce, Rovingaile Kriska; Thomas, Norman; Bui, Nam Q.; Kondo, Tadashi; Okimoto, Ross A.

doi:10.1172/jci.insight.152293

Cited by 11 publications

(9 citation statements)

References 45 publications

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“…To further understand the key pathways that CIC-DUX4 regulates to promote tumor progression, we performed gene ontology (GO) using the DAVID (20) and PANTHER (21) tools. We found that CIC-DUX4 mediates multiple pathways associated with cell cycle and DNA replication and repair, which is consistent with prior studies (22). We next performed an integrative RNA-Seq and ChIP-Seq based analysis to identify both known and novel CIC-DUX4 target genes.…”

Section: Resultssupporting

confidence: 93%

Mapping chromatin state and transcriptional response in CIC-DUX4 undifferentiated round cell sarcoma

Thomas,

Luck,

Shlimon

et al. 2023

Preprint

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CIC-DUX4 is a rare and understudied transcription factor fusion oncoprotein. CIC-DUX4 co-opts native gene targets to drive a lethal form of human sarcoma. The molecular underpinnings that lead to oncogenic reprograming and CIC-DUX4 sarcomagenesis remain largely undefined. Through an integrative ChIP and RNA-Seq analysis using patient-derived CIC-DUX4 cells, we define CIC-DUX4 mediated chromatin states and function. We show that CIC-DUX4 primarily localizes to proximal and distal cis-regulatory elements where it associates with active histone marks. Our findings nominate key signaling pathways and molecular targets that enable CIC-DUX4 to mediate tumor cell survival. Collectively, our data demonstrate how the CIC-DUX4 fusion oncoprotein impacts chromatin state and transcriptional responses to drive an oncogenic program in undifferentiated sarcoma.

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Section: Resultssupporting

confidence: 93%

Mapping chromatin state and transcriptional response in CIC-DUX4 undifferentiated round cell sarcoma

Thomas,

Luck,

Shlimon

et al. 2023

Preprint

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“…Oncogenic fusion genes encoding aberrant transcription factors are drivers of replication stress (43,37), as shown in previous studies in PAX::FOXO1-driven rhabdomyosarcoma, CIC::DUX4-expressing sarcoma and Ewing sarcoma harboring EWSR1::FLI1 fusion oncoproteins (34)(35)(36). Consistently, FUS::DDIT3 expression in a mesenchymal stem cell model system was sufficient to accelerate cell cycle progression and to induce cellular stress.…”

Section: Discussionsupporting

confidence: 81%

Exploiting WEE1 kinase activity as FUS::DDIT3-dependent therapeutic vulnerability in myxoid liposarcoma

Heinst,

Lee,

Berthold

et al. 2024

Preprint

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The pathognomonic FUS::DDIT3 fusion protein drives myxoid liposarcoma (MLS) tumorigenesis via aberrant transcriptional activation of oncogenic signaling. Since FUS::DDIT3 has so far not been pharmacologically tractable to selectively target MLS cells, this study investigated the functional role of the cell cycle regulator WEE1 as novel FUS::DDIT3-dependent therapeutic vulnerability in MLS. Here we demonstrate that enhanced WEE1 pathway activity represents a hallmark of FUS::DDIT3-expressing cell lines as well as MLS tissue specimens and that WEE1 is required for MLS cellular survivalin vitroandin vivo. Pharmacologic inhibition of WEE1 activity results in DNA damage accumulation and cell cycle progression forcing cells to undergo apoptotic cell death. In addition, our results uncover FUS::DDIT3-dependent WEE1 expression as an oncogenic survival mechanism to tolerate high proliferation and resulting replication stress in MLS. Fusion protein-driven G1/S cell cycle checkpoint deregulation via overactive Cyclin E/CDK2 complexes thereby contributes to enhanced WEE1 inhibitor sensitivity in MLS. These findings identify WEE1-mediated replication stress tolerance as molecular vulnerability in FUS::DDIT3-driven MLS tumorigenesis that could represent a novel target for therapeutic intervention.

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“…The finding was supported by the result that the treatment with the p300/CBP inhibitor iP300w inhibited the proliferation of CIC::DUX4 sarcoma cells 111 . CIC::DUX4 upregulates genes of oncogenic pathways such as ETV1/4/5 and Cyclin D/E 112,113 . The regulator of the G2/M checkpoint, WEE1, was identified as a potential therapeutic target of CIC::DUX4‐induced cell cycle progression.…”

Section: Epigenetic Aberrations In Bone and Soft Tissue Sarcomas And ...mentioning

confidence: 86%

“…111 CIC::DUX4 upregulates genes of oncogenic pathways such as ETV1/4/5 and Cyclin D/E. 112,113 The regulator of the G2/M checkpoint, WEE1, was identified as a potential therapeutic target of CIC::DUX4induced cell cycle progression.…”

Section: Cic-rearranged Sarcomamentioning

confidence: 99%

Targeting epigenetic aberrations of sarcoma in CRISPR era

Tanaka

Nakamura

2023

Genes Chromosomes & Cancer

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Sarcomas are rare malignancies that exhibit diverse biological, genetic, morphological, and clinical characteristics. Genetic alterations, such as gene fusions, mutations in transcriptional machinery components, histones, and DNA methylation regulatory molecules, play an essential role in sarcomagenesis. These mutations induce and/or cooperate with specific epigenetic aberrations required for the growth and maintenance of sarcomas. Appropriate mouse models have been developed to clarify the significance of genetic and epigenetic interactions in sarcomas. Studies using the mouse models for human sarcomas have demonstrated major advances in our understanding the developmental processes as well as tumor microenvironment of sarcomas. Recent technological progresses in epigenome editing will not only improve the studies using animal models but also provide a direct clue for epigenetic therapies. In this manuscript, we review important epigenetic aberrations in sarcomas and their representative mouse models, current methods of epigenetic editing using CRISPR/ dCas9 systems, and potential applications in sarcoma studies and therapeutics.

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

Cited by 11 publications

References 45 publications

Mapping chromatin state and transcriptional response in CIC-DUX4 undifferentiated round cell sarcoma

Mapping chromatin state and transcriptional response in CIC-DUX4 undifferentiated round cell sarcoma

Exploiting WEE1 kinase activity as FUS::DDIT3-dependent therapeutic vulnerability in myxoid liposarcoma

Targeting epigenetic aberrations of sarcoma in CRISPR era

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