Rhabdoid Tumors Are Sensitive to the Protein-Translation Inhibitor Homoharringtonine.

Autor:	Howard TP; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Oberlick EM; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Rees MG; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Arnoff TE; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Pham MT; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Brenan L; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., DoCarmo M; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Hong AL; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Department of Pediatrics, Emory University, Atlanta, Georgia., Kugener G; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Chou HC; Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee.; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Drosos Y; Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee.; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Mathias KM; Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee.; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Ramos P; Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee.; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Seashore-Ludlow B; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Giacomelli AO; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Wang X; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.; Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire., Freeman BB 3rd; Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, Memphis, Tennessee., Blankenship K; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Hoffmann L; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Tiv HL; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Gokhale PC; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Johannessen CM; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Stewart EA; Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee. charles.roberts@stjude.org elizabeth.stewart@stjude.org william_hahn@dfci.harvard.edu.; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee., Schreiber SL; Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts., Hahn WC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. charles.roberts@stjude.org elizabeth.stewart@stjude.org william_hahn@dfci.harvard.edu.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Roberts CWM; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts. charles.roberts@stjude.org elizabeth.stewart@stjude.org william_hahn@dfci.harvard.edu.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee.; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Sep 15; Vol. 26 (18), pp. 4995-5006. Date of Electronic Publication: 2020 Jul 06.
DOI:	10.1158/1078-0432.CCR-19-2717
Abstrakt:	Purpose: Rhabdoid tumors are devastating pediatric cancers in need of improved therapies. We sought to identify small molecules that exhibit in vitro and in vivo efficacy against preclinical models of rhabdoid tumor. Experimental Design: We screened eight rhabdoid tumor cell lines with 481 small molecules and compared their sensitivity with that of 879 other cancer cell lines. Genome-scale CRISPR-Cas9 inactivation screens in rhabdoid tumors were analyzed to confirm target vulnerabilities. Gene expression and CRISPR-Cas9 data were queried across cell lines and primary rhabdoid tumors to discover biomarkers of small-molecule sensitivity. Molecular correlates were validated by manipulating gene expression. Subcutaneous rhabdoid tumor xenografts were treated with the most effective drug to confirm in vitro results. Results: Small-molecule screening identified the protein-translation inhibitor homoharringtonine (HHT), an FDA-approved treatment for chronic myelogenous leukemia (CML), as the sole drug to which all rhabdoid tumor cell lines were selectively sensitive. Validation studies confirmed the sensitivity of rhabdoid tumor to HHT was comparable with that of CML cell lines. Low expression of the antiapoptotic gene BCL2L1 , which encodes Bcl-XL, was the strongest predictor of HHT sensitivity, and HHT treatment consistently depleted Mcl-1, the synthetic-lethal antiapoptotic partner of Bcl-XL. Rhabdoid tumor cell lines and primary-tumor samples expressed low BCL2L1 , and overexpression of BCL2L1 induced resistance to HHT in rhabdoid tumor cells. Furthermore, HHT treatment inhibited rhabdoid tumor cell line and patient-derived xenograft growth in vivo . Conclusions: Rhabdoid tumor cell lines and xenografts are highly sensitive to HHT, at least partially due to their low expression of BCL2L1 . HHT may have therapeutic potential against rhabdoid tumors. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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