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Identification of Therapeutic Targets in Rhabdomyosarcoma through Integrated Genomic, Epigenomic, and Proteomic Analyses.


ABSTRACT: Personalized cancer therapy targeting somatic mutations in patient tumors is increasingly being incorporated into practice. Other therapeutic vulnerabilities resulting from changes in gene expression due to tumor specific epigenetic perturbations are progressively being recognized. These genomic and epigenomic changes are ultimately manifest in the tumor proteome and phosphoproteome. We integrated transcriptomic, epigenomic, and proteomic/phosphoproteomic data to elucidate the cellular origins and therapeutic vulnerabilities of rhabdomyosarcoma (RMS). We discovered that alveolar RMS occurs further along the developmental program than embryonal RMS. We also identified deregulation of the RAS/MEK/ERK/CDK4/6, G2/M, and unfolded protein response pathways through our integrated analysis. Comprehensive preclinical testing revealed that targeting the WEE1 kinase in the G2/M pathway is the most effective approach in vivo for high-risk RMS.

SUBMITTER: Stewart E 

PROVIDER: S-EPMC6158019 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Identification of Therapeutic Targets in Rhabdomyosarcoma through Integrated Genomic, Epigenomic, and Proteomic Analyses.

Stewart Elizabeth E   McEvoy Justina J   Wang Hong H   Chen Xiang X   Honnell Victoria V   Ocarz Monica M   Gordon Brittney B   Dapper Jason J   Blankenship Kaley K   Yang Yanling Y   Li Yuxin Y   Shaw Timothy I TI   Cho Ji-Hoon JH   Wang Xusheng X   Xu Beisi B   Gupta Pankaj P   Fan Yiping Y   Liu Yu Y   Rusch Michael M   Griffiths Lyra L   Jeon Jongrye J   Freeman Burgess B BB   Clay Michael R MR   Pappo Alberto A   Easton John J   Shurtleff Sheila S   Shelat Anang A   Zhou Xin X   Boggs Kristy K   Mulder Heather H   Yergeau Donald D   Bahrami Armita A   Mardis Elaine R ER   Wilson Richard K RK   Zhang Jinghui J   Peng Junmin J   Downing James R JR   Dyer Michael A MA  

Cancer cell 20180823 3


Personalized cancer therapy targeting somatic mutations in patient tumors is increasingly being incorporated into practice. Other therapeutic vulnerabilities resulting from changes in gene expression due to tumor specific epigenetic perturbations are progressively being recognized. These genomic and epigenomic changes are ultimately manifest in the tumor proteome and phosphoproteome. We integrated transcriptomic, epigenomic, and proteomic/phosphoproteomic data to elucidate the cellular origins a  ...[more]

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