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Shah, V.J.* ; Hartmann, O. ; Wegner, M.* ; Prieto-Garcia, C.* ; Kazi, R.* ; von Heyl zu Herrnsheim, V. ; Wanli, A.* ; Mačinković, I.* ; Bohnacker, B. ; Husnjak, K.* ; Namgaladze, D.* ; Rosenfeldt, M.* ; Kaulich, M.* ; Diefenbacher, M. ; Dikic, I.*

Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer.

EMBO J. 45, 3276-3305 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Lung cancer cells rely on protein homeostasis regulators, particularly the ubiquitin-proteasome system (UPS), to sustain malignancy. Genetic alterations in UPS components, such as E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), are common and create context-dependent therapeutic dependencies. To investigate how these genetic alterations drive tumor formation, we conducted CRISPR screens on metabolically stressed murine lung cancer models and identified specific cancer dependencies, including ubiquitin ligase subunit KEAP1. Although KEAP1 is frequently mutated in aggressive non-small cell lung cancers (NSCLC, ~15%), our findings reveal an unexpected proto-oncogenic role for KEAP1 in a genetically defined subset of NSCLC. Mechanistically, Keap1 deletion activated Nrf2 and upregulated Aldh3a1. This led to elevated reductive stress and suppressed tumor growth. Given the poor prognosis of KEAP1-mutated patients, combinatorial CRISPR dropout screens revealed druggable E3s and DUBs as Keap1-dependent co-vulnerabilities. Notably, depleting these co-dependencies, such as the E3 ligases Herc2, Ubr4 and Huwe1 ablated the in vivo development of Keap1-inactivated tumors. We demonstrate that targeting the UPS represents an underexplored, promising therapeutic approach for patients with KEAP1-inactivated tumors, especially under metabolic stress.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Crispr/cas9 ; Keap1 ; Nsclc ; Reductive Stress ; Ubiquitin-proteasome System; Stress; Nrf2; Pathway
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Quellenangaben Band: 45, Heft: 9, Seiten: 3276-3305 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Heidelberg, Germany
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)
Förderungen Deutsche Forschungsgemeinschaft (DFG)