BIRC2\u2013BIRC3 amplification: a potentially druggable feature of a subset of head and neck cancers in patients with Fanconi anemia

Khashayar Roohollahi,Yvonne De Jong,Daoud Sie,Rob Wolthuis,Najim Ameziane,Martin A Rooimans,Elizabeth E Hoskins,Josephine Dorsman,Klaas De Lint,Susanne I Wells,Hans Joenje,Mohamad Amr Zaini,Davy Rockx,Govind Pai

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.

Highlights

Head-and-neck squamous cell carcinomas (HNSCCs) are relatively common in patients with Fanconi anemia (FA), a hereditary chromosomal instability disorder
TP53 is the only gene mutated in the majority of FA-HNSCC derived cells with four out of six having missense or frameshift mutations This is in accord with the TCGA sporadic HNSCC cohort data (n = 278), where TP53 was the most frequently mutated gene (Fig. 1b)
A total of three out of four TP53 mutations in FA-HNSCC cell lines reside in the TP53 DNA-binding domain, while one mutation was located in the transactivation domain (Fig. 1c)

Summary

Introduction

Head-and-neck squamous cell carcinomas (HNSCCs) are relatively common in patients with Fanconi anemia (FA), a hereditary chromosomal instability disorder. 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 found the drug AZD5582, a known small molecule inhibitor of BIRC2-3, to selectively kill FA tumor cells that overexpressed BIRC2-3. Due to the hypersensitivity of all somatic cells of FA patients to ICLs, this standard cancer treatment often causes severe and potentially fatal side effects in FA patients[4,5]. (a) Oncoplot for top frequently mutated genes in FA-HNSCC tumor cells (≥ 33%). Node sizes are adjusted based on the occurrence of the mutations in FA-HNSCC. Apoptotic/cellular senescence are the major mutated pathways in FA-HNSCCs. Apart from TP53, other pathway-associated genes are mutated in a cell line-specific fashion

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