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

Purpose: Rhabdoid tumors (RTs) 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 RT. Experimental Design: We screened eight RT cell lines with 481 small molecules and compared their sensitivity to that of 879 other cancer cell lines. Genome-scale CRISPR-Cas9 inactivation screens in RTs were analyzed to confirm target vulnerabilities. Gene expression and CRISPR-Cas9 data were queried across cell lines and primary RTs to discover biomarkers of small-molecule sensitivity. Molecular correlates were validated by manipulating gene expression. Subcutaneous RT 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 RT cell lines were selectively sensitive. Validation studies confirmed the sensitivity of RTs to HHT was comparable to 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. RT cell lines and primary-tumor samples expressed low BCL2L1, and overexpression of BCL2L1 induced resistance to HHT in RT cells. Furthermore, HHT treatment inhibited RT cell line and patient derived xenograft growth in vivo. Conclusions: RT 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 RTs.