somatic hypersensitivity
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2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Khashayar Roohollahi ◽  
Yvonne de Jong ◽  
Govind Pai ◽  
Mohamad Amr Zaini ◽  
Klaas de Lint ◽  
...  

AbstractHead-and-neck squamous cell carcinomas (HNSCCs) are relatively common in patients with Fanconi anemia (FA), a hereditary chromosomal instability disorder. Standard chemo-radiation therapy is not tolerated in FA due to an overall somatic hypersensitivity to such treatment. The question is how to find a suitable alternative treatment. We used whole-exome and whole genome mRNA sequencing to identify major genomic and transcriptomic events associated with FA-HNSCC. CRISPR-engineered FA-knockout models were used to validate a number of top hits that were likely to be druggable. We identified deletion of 18q21.2 and amplification of 11q22.2 as prevailing copy-number alterations in FA HNSCCs, the latter of which was associated with strong overexpression of the cancer-related genes YAP1, BIRC2, BIRC3 (at 11q22.1-2). We then found the drug AZD5582, a known small molecule inhibitor of BIRC2-3, to selectively kill FA tumor cells that overexpressed BIRC2-3. This occurred at drug concentrations that did not affect the viability of untransformed FA cells. Our data indicate that 11q22.2 amplifications are relatively common oncogenic events in FA-HNSCCs, as holds for non FA-HNSCC. Therefore, chemotherapeutic inhibition of overexpressed BIRC2-3 may provide the basis for an approach to develop a clinically realistic treatment of FA-HNSCCs that carry 11q22.2 amplifications.


2018 ◽  
Vol 34 (10) ◽  
pp. 944-949 ◽  
Author(s):  
QiQi Zhou ◽  
Meghan L. Verne ◽  
Buyi Zhang ◽  
G. Nicholas Verne

2012 ◽  
Vol 142 (5) ◽  
pp. S-137 ◽  
Author(s):  
Clive H Wilder-Smith ◽  
Cao Yang ◽  
Xinhua Li ◽  
Khek-Yu Ho ◽  
Reuben K. Wong

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