Fanconi anemia pathway disruption drives lomustine sensitivity in glioma.

IF 13.1 1区医学 Q1 CLINICAL NEUROLOGY

Neuro-oncology Pub Date : 2026-10-10 DOI:10.1093/neuonc/noag254

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 Tatagiba, Sven Nahnsen, Manfred Claassen, Reka Haraszti, Frank Szulzewsky, Eric C Holland, Daniel Josef Merk, Ghazaleh Tabatabai

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引用次数: 0

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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范可尼贫血通路破坏驱动脑胶质瘤中的洛莫司汀敏感性。

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来源期刊

Neuro-oncology 医学-临床神经学

CiteScore

27.20

自引率

6.30%

发文量

1434

审稿时长

3-8 weeks

期刊介绍： Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.