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

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

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5 Citations (Scopus)


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.

Original languageEnglish
Article number45
Pages (from-to)45
JournalScientific reports
Issue number1
Publication statusPublished - 7 Jan 2022


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

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