BIRC2-BIRC3 amplification: a potentially druggable feature of a subset of head and neck cancers in patients with Fanconi anemia.

Abstract

Head-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.

• Authors: Khashayar Roohollahi, Yvonne de Jong, Govind Pai, Mohamad Amr Zaini, Klaas de Lint, Daoud Sie, Martin A Rooimans, Davy Rockx, Elizabeth E Hoskins, Najim Ameziane, Rob Wolthuis, Hans Joenje, Susanne I Wells, Josephine Dorsman
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 45 (01 07 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 34997070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Alkynes
• Inhibitor of Apoptosis Proteins
• Intracellular Signaling Peptides and Proteins
• N,N'-(2,2'-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(1-(2-cyclohexyl-2-(2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamide)
• Oligopeptides
• Receptors, Cell Surface
• TMEM123 protein, human
• YAP-Signaling Proteins
• YAP1 protein, human
• BIRC2 protein, human
• BIRC3 protein, human
• Baculoviral IAP Repeat-Containing 3 Protein
• Ubiquitin-Protein Ligases

Topics

• Alkynes (pharmacology)
• Baculoviral IAP Repeat-Containing 3 Protein (antagonists & inhibitors, genetics, metabolism)
• Cell Line
• Cell Survival (drug effects, genetics)
• DNA Copy Number Variations
• DNA Mutational Analysis
• Fanconi Anemia (complications, drug therapy, genetics, immunology)
• Gene Expression Regulation, Neoplastic
• Head and Neck Neoplasms (complications, drug therapy, genetics, immunology)
• Humans
• Inhibitor of Apoptosis Proteins (antagonists & inhibitors, genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Oligopeptides (pharmacology)
• Receptors, Cell Surface (genetics, metabolism)
• Ubiquitin-Protein Ligases (antagonists & inhibitors, genetics, metabolism)
• YAP-Signaling Proteins (genetics, metabolism)