Neuro-oncology · 2026
Fanconi anemia pathway disruption drives lomustine sensitivity in glioma.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Becker Hannes, Walter Bianca, Haeusser Lara Annina, Trampert Jil, Zago Marcello, Surender Surender, Maise Louise, Volos Polina, Erdmann Sarah, Kuhlburger Laurence, Falkner Aaron, Tsiami Foteini, Dörner Lorenz, Maric Marko, Skotnicki Albert, Jägle Hannes, Echeverria Dimas, Jackson Samual, Tripathi Ansh, Segarra-Visent Xavier, Bhandari Anushka, Beck Susanne, Tatagiba Marcos, Nahnsen Sven, Claassen Manfred, Haraszti Reka, Szulzewsky Frank, Holland Eric C, Merk Daniel Josef, Tabatabai Ghazaleh
Аннотация
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.
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.