Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer - PubMed
5 hours ago
- #KEAP1
- #NSCLC
- #Ubiquitin-Proteasome System
- Lung cancer cells depend on the ubiquitin-proteasome system (UPS) for malignancy.
- CRISPR screens identified KEAP1 as a critical dependency in metabolically stressed lung cancer models.
- KEAP1 mutations are common in aggressive NSCLC (~15%) and exhibit a proto-oncogenic role.
- Keap1 deletion activates Nrf2 and upregulates Aldh3a1, leading to reductive stress and suppressed tumor growth.
- Combinatorial CRISPR screens revealed druggable E3 ligases (Herc2, Ubr4, Huwe1) and DUBs as co-vulnerabilities in KEAP1-inactivated tumors.
- Targeting UPS components presents a promising therapeutic strategy for KEAP1-mutated NSCLC patients.