Genome-wide siRNA screens identify RBBP9 function as a potential target in Fanconi anaemia-deficient head-and-neck squamous cell carcinoma

• Published in: Communications biology 2023-01, Vol.6 (1), p.37-12, Article 37
• Main Authors: Pai, Govind, Roohollahi, Khashayar, Rockx, Davy, de Jong, Yvonne, Stoepker, Chantal, Pennings, Charlotte, Rooimans, Martin, Vriend, Lianne, Piersma, Sander, Jimenez, Connie R., De Menezes, Renee X., Van Beusechem, Victor W., Brakenhoff, Ruud H., Te Riele, Hein, Wolthuis, Rob M. F., Dorsman, Josephine C.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/2; 13/31; 13/89; 631/208/69; 631/67/1536/1665; Anemia; Biology; Biomedical and Life Sciences; Cell Cycle Proteins - genetics; Cisplatin; DNA; DNA repair; Emetine; Emetine - therapeutic use; Fanconi Anemia - genetics; Fanconi Anemia - pathology; Fanconi syndrome; Genetic screening; Genome-Wide Association Study; Genomes; Head and neck carcinoma; Head and Neck Neoplasms; Humans; Intolerance; Intracellular Signaling Peptides and Proteins - genetics; Lethality; Life Sciences; Neoplasm Proteins - genetics; RNA, Small Interfering - genetics; siRNA; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - genetics; Therapeutic targets; Toxicity; Tumor cell lines; Tumors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-04389-3

Fanconi anaemia (FA) is a rare chromosomal-instability syndrome caused by mutations of any of the 22 known FA DNA-repair genes. FA individuals have an increased risk of head-and-neck squamous-cell-carcinomas (HNSCC), often fatal. Systemic intolerance to standard cisplatin-based protocols due to somatic-cell hypersensitivity underscores the urgent need to develop novel therapies. Here, we performed unbiased siRNA screens to unveil genetic interactions synthetic-lethal with FA-pathway deficiency in FA-patient HNSCC cell lines. We identified based on differential-lethality scores between FA-deficient and FA-proficient cells, next to common-essential genes such as PSMC1, PSMB2, and LAMTOR2, the otherwise non-essential RBBP9 gene. Accordingly, low dose of the FDA-approved RBBP9-targeting drug Emetine kills FA-HNSCC. Importantly both RBBP9-silencing as well as Emetine spared non-tumour FA cells. This study provides a minable genome-wide analyses of vulnerabilities to address treatment challenges in FA-HNSCC. Our investigation divulges a DNA-cross-link-repair independent lead, RBBP9, for targeted treatment of FA-HNSCCs without systemic toxicity. A genome-wide siRNA screen on patient-derived Fanconi anemia pathway-deficient head-and-neck squamous-cell-carcinoma (HNSCC) cell lines identifies RBBP9 as a candidate therapeutic target.