Aurora kinase A is a synthetic lethal target in FANCA-deficient cancers
8 affiliations
- 1Department of Medical Oncology, Inselspital, University Hospital of Bern, University of Bern, Bern, Switzerland
- 2Department for BioMedical Research, University of Bern, Bern, Switzerland
- 3Bern Center for Precision Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland
- 4Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- 5Department of Medical Oncology and Hematology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
- 6Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
- 7Cancer Genomics Research, Foundation Medicine Inc., Boston, MA USA
- 8Genetic Perturbation Platform, Broad Institute, Cambridge, MA USA
Abstract
Loss-of-function genomic alterations in FANCA occur across multiple cancer types, yet no molecularly tailored therapies have successfully exploited this potential vulnerability. Using complementary unbiased approaches, including a genome-wide CRISPR/Cas9 loss-of-function screen and a high-throughput drug screen in isogenic cancer cell-based models, we identified Aurora kinase A (AURKA) as a reproducible synthetic lethal target of FANCA-deficient cancers. Inhibition of AURKA induced chromosomal instability, micronucleation, and differential mitotic dynamics dependent on FANCA status. Mechanistically, FANCA deficiency is associated with an elevated AURKA expression at both the transcriptomic and protein levels, and with an upregulation of mitotic spindle and G2/M checkpoint gene signatures. Analysis of large-scale cancer genomics datasets, including over 650,000 clinically sequenced tumors, confirms that FANCA is the most frequently altered Fanconi anemia pathway gene across cancers, and that Fanconi anemia–defective tumors exhibit an increased tumor mutational burden and genomic instability. Collectively, our findings point to AURKA inhibition as a promising precision treatment strategy in FANCA-deficient cancers and provide a rationale to further explore this strategy in the clinic.
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BibTeX
@article{akhoundova2026aurora,
title = {{Aurora kinase A is a synthetic lethal target in FANCA-deficient cancers}},
author = {Dilara Akhoundova and Martín González-Fernández and Aavash Baral and Andrej Benjak and Carmen Perry and Dinda Shezaria Hardy Lubis and Ladina Hörtensteiner and Saskia Hussung and Lea Lingg and Sina Maletti and Aino Paasinen-Sohns and Marika Lehner and Bastian Dislich and Erik Vassella and Simone de Brot and Therese Waldburger and Petros Tsiridis and Carmen Cardozo and Ralph Fritsch and Clelia Pistoni and Seynabou Diop and Phillip Thienger and Taina Kaiponen and Muriel Jaquet and Mariana Ricca and Smruthy Sivakumar and Christopher McDermott-Roe and David E. Root and Paola Francica and Sven Rottenberg and Mark A. Rubin},
journal = {NPJ Precision Oncology},
year = {2026},
month = jul,
doi = {10.1038/s41698-026-01596-7},
url = {https://doi.org/10.1038/s41698-026-01596-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Aurora kinase A is a synthetic lethal target in FANCA-deficient cancers
AU - Dilara Akhoundova
AU - Martín González-Fernández
AU - Aavash Baral
AU - Andrej Benjak
AU - Carmen Perry
AU - Dinda Shezaria Hardy Lubis
AU - Ladina Hörtensteiner
AU - Saskia Hussung
AU - Lea Lingg
AU - Sina Maletti
AU - Aino Paasinen-Sohns
AU - Marika Lehner
AU - Bastian Dislich
AU - Erik Vassella
AU - Simone de Brot
AU - Therese Waldburger
AU - Petros Tsiridis
AU - Carmen Cardozo
AU - Ralph Fritsch
AU - Clelia Pistoni
AU - Seynabou Diop
AU - Phillip Thienger
AU - Taina Kaiponen
AU - Muriel Jaquet
AU - Mariana Ricca
AU - Smruthy Sivakumar
AU - Christopher McDermott-Roe
AU - David E. Root
AU - Paola Francica
AU - Sven Rottenberg
AU - Mark A. Rubin
PY - 2026
DA - 2026/07/11
JO - NPJ Precision Oncology
DO - 10.1038/s41698-026-01596-7
UR - https://doi.org/10.1038/s41698-026-01596-7
AB - Loss-of-function genomic alterations in FANCA occur across multiple cancer types, yet no molecularly tailored therapies have successfully exploited this potential vulnerability. Using complementary unbiased approaches, including a genome-wide CRISPR/Cas9 loss-of-function screen and a high-throughput drug screen in isogenic cancer cell-based models, we identified Aurora kinase A (AURKA) as a reproducible synthetic lethal target of FANCA-deficient cancers. Inhibition of AURKA induced chromosomal instability, micronucleation, and differential mitotic dynamics dependent on FANCA status. Mechanistically, FANCA deficiency is associated with an elevated AURKA expression at both the transcriptomic and protein levels, and with an upregulation of mitotic spindle and G2/M checkpoint gene signatures. Analysis of large-scale cancer genomics datasets, including over 650,000 clinically sequenced tumors, confirms that FANCA is the most frequently altered Fanconi anemia pathway gene across cancers, and that Fanconi anemia–defective tumors exhibit an increased tumor mutational burden and genomic instability. Collectively, our findings point to AURKA inhibition as a promising precision treatment strategy in FANCA-deficient cancers and provide a rationale to further explore this strategy in the clinic.
SN - 2397-768X
ER -