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

Sci Rep. 2022 Jan 7;12(1):45. doi: 10.1038/s41598-021-04042-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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