Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer.
Shah Varun Jayeshkumar, Hartmann Oliver, Wegner Martin, Prieto-Garcia Cristian, Kazi Rubina, von Heyl Zu Herrnsheim Viktoria, Wanli Amin, Mačinković Igor, Bohnacker Bianka, Husnjak Koraljka, Namgaladze Dmitry, Rosenfeldt Mathias, Kaulich Manuel, Diefenbacher Markus E, Dikic Ivan
Abstract
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.
Key Findings
- KEAP1 deletion activates NRF2 and upregulates Aldh3a1, leading to elevated reductive stress and suppressed tumor growth in a subset of NSCLC.
- KEAP1-inactivated lung cancers show dependencies on specific ubiquitin ligases and deubiquitinating enzymes, such as Herc2, Ubr4, and Huwe1.
- Targeting the ubiquitin-proteasome system (UPS) components represents a promising therapeutic strategy for KEAP1-mutated lung cancers, especially under metabolic stress.
Clinical Significance
This study identifies novel druggable vulnerabilities in KEAP1-inactivated non-small cell lung cancer, suggesting that targeting ubiquitin signaling pathways could improve treatment outcomes for patients with poor prognosis due to KEAP1 mutations.
Citation
Shah Varun Jayeshkumar, Hartmann Oliver, Wegner Martinet al.. Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer. The EMBO journal. 2026-Mar-20.