Rhabdoid Tumors Are Sensitive to the Protein-Translation Inhibitor Homoharringtonine:
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.
Σφακιανάκης Αλέξανδρος
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5 Άγιος Νικόλαος
Κρήτη 72100
00302841026182
00306932607174
alsfakia@gmail.com
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- International Journal of Molecular Sciences
- Antibiotics
- Spiritual care experiences by cancer pati
- Focused ultrasound robotic system for v
- Macrophage HIF-1{alpha} Is an Independent Prognost...
- Radiation with STAT3 Blockade Triggers Dendritic C...
- Rhabdoid Tumors Are Sensitive to the Protein-Trans...
- Tumor Subtype Determines Therapeutic Response to C...
- Editor's Note: The Pivotal Role of Integrin {beta}...
- Clinical variability in spinal muscular atrophy ty...
- Clinical Balance Testing to Screen for Patients Wi...
- The effectiveness of radiotherapy in the treatment...
- Prophet forecasting model: a machine learning appr...
- TET1 may contribute to hypoxia-induced epithelial ...
- Correlation of Radiologic Versus Endoscopic Visual...
- Consequences of Mastoidectomy on Bone Conducted So...
- Laterality of Audiovestibular Symptoms Predicts La...
- Visualizing Affected Nerve Bundles of Cranial Nerv...
- Malformations Associated With Pediatric Congenital...
- Definitive treatment of sporadic vestibular schwan...
- Long-term survival after cemented versus uncemente...
- giant retroperitoneal neurilemmoma
- Resveratrol prevents TNF-α-induced VCAM-1 and ICAM...
- Vocal trauma especially in females and children is...
- Brazilian butt lift (BBL) surgery
- Adipose-derived stem cell enrichment is counter-pr...
- Cognitive, language and motor development of infan...
- Prolonged Survival of a Patient with Chronic Myelo...
- Correlation between the Epworth Sleepiness Scale a...
- Iron induces cell death and strengthens the effica...
- Flumatinib versus Imatinib for Newly Diagnosed Chr...
- Immediate inhibition of spinal secretory phospholi...
- Eriodictyol produces antidepressant-like effects a...
- Electroacupuncture at GV24 and bilateral GB13 impr...
- Minimal incision superficialization of the brachia...
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