Rhabdoid Tumors Are Sensitive to the Protein-Translation Inhibitor Homoharringtonine
Rhabdoid tumors are devastating pediatric cancers in need of improved therapies. We sought to identify small molecules that exhibit and efficacy against preclinical models of rhabdoid tumor. We screened eight rhabdoid tumor cell lines with 481 small molecules and compared their sensitivity with that...
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Veröffentlicht in: | Clinical cancer research 2020-09, Vol.26 (18), p.4995-5006 |
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Sprache: | eng |
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Zusammenfassung: | Rhabdoid tumors are devastating pediatric cancers in need of improved therapies. We sought to identify small molecules that exhibit
and
efficacy against preclinical models of rhabdoid tumor.
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
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
, 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
, and overexpression of
induced resistance to HHT in rhabdoid tumor cells. Furthermore, HHT treatment inhibited rhabdoid tumor cell line and patient-derived xenograft growth
.
Rhabdoid tumor cell lines and xenografts are highly sensitive to HHT, at least partially due to their low expression of
. HHT may have therapeutic potential against rhabdoid tumors. |
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ISSN: | 1078-0432 1557-3265 1557-3265 |
DOI: | 10.1158/1078-0432.ccr-19-2717 |