Fanconi anemia pathway disruption drives lomustine sensitivity in glioma

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ID: 332018
2026
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Abstract
Abstract 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.
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Authors Hannes Becker, Bianca Walter, Lara Annina Haeusser, Jil Trampert, Marcello Zago, Surender Surender, Louise Maise, Polina Volos, Sarah Erdmann, Laurence Kuhlburger, Aaron Falkner, Foteini Tsiami, Lorenz Dörner, Marko Maric, Albert Skotnicki, Hannes Jägle, Dimas Echeverria, Samual Jackson, Ansh Tripathi, Xavier Segarra-Visent, Anushka Bhandari, Susanne Beck, Marcos Soares Tatagiba, Sven Nahnsen, Manfred Claassen, Réka Ágnes Haraszti, Frank Szulzewsky, Eric C. Holland, Daniel Josef Merk, Ghazaleh Tabatabai
Journal journal of neuro-oncology
Year 2026
DOI
10.1093/neuonc/noag254
URL
https://doi.org/10.1093/neuonc/noag254
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