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Fanconi anemia pathway disruption drives lomustine sensitivity in glioma
Hannes Becker1,2,3,4, Bianca Walter1,2, Lara Annina Haeusser1,2,5
1Department of Neurology & Interdisciplinary Neuro-Oncology, University Hospital Tübingen, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Background:
Therapeutic options for progressive glioblastoma remain limited, with chlorethyl-cyclohexyl-nitrosourea (CCNU, lomustine) among the approved treatments. Beyond MGMT gene promoter methylation, molecular determinants of CCNU sensitivity or resistance are ill- defined.
Methods:
We employed genome-wide functional knockout screening using the CRISPR-Cas9 technology to identify and subsequently validate modulators of response to CCNU in experimental glioma. We established an immunocompetent glioma mouse model to enable functional interrogation of Fanconi anemia pathway (FA) genes in tumor growth and synthetic lethal interactions in vivo using the RCAS/tv-a somatic gene delivery system.
Results:
Multiple FA pathway members recurrently emerged as potent synthetic lethal interactors of CCNU treatment. In vivo knockdown of Fancm accelerated tumor onset and significantly increased CCNU sensitivity. Consistently, FA pathway inhibition enhanced CCNU efficacy across in vitro, ex vivo and in vivo models.
Conclusion:
Together, these findings identify FA pathway components as key synthetic lethal interactors of CCNU response and reveal a therapeutically actionable vulnerability in glioblastoma.