Related Experiment Video

Updated: Mar 22, 2026

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

18.8K

Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer

Varun Jayeshkumar Shah1, Oliver Hartmann2,3,4, Martin Wegner1

  • 1Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt am Main, Germany.

The EMBO Journal
|March 21, 2026
PubMed

Insights

KEAP1 mutations in lung cancer unexpectedly promote tumors by activating Nrf2. Targeting the ubiquitin-proteasome system (UPS) offers a novel therapeutic strategy for KEAP1-mutated non-small cell lung cancer (NSCLC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Lung cancer malignancy depends on protein homeostasis, regulated by the ubiquitin-proteasome system (UPS).
  • Genetic alterations in UPS components like E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) are common in cancer, creating therapeutic vulnerabilities.
  • KEAP1 mutations occur in approximately 15% of aggressive non-small cell lung cancers (NSCLC).

Purpose of the Study:

  • To investigate how genetic alterations in UPS components drive tumor formation in lung cancer.
  • To identify context-dependent cancer dependencies and potential therapeutic targets in metabolically stressed lung cancer models.
  • To explore the proto-oncogenic role of KEAP1 in a specific subset of NSCLC.

Main Methods:

  • Conducted CRISPR screens on metabolically stressed murine lung cancer models.
  • Utilized CRISPR dropout screens to identify Keap1-dependent co-vulnerabilities.
  • Investigated the mechanistic link between Keap1 inactivation, Nrf2 activation, and tumor growth suppression.

Main Results:

  • Identified KEAP1 as a specific cancer dependency in lung cancer models.
  • Revealed an unexpected proto-oncogenic role for KEAP1, where its deletion suppressed tumor growth by activating Nrf2 and upregulating Aldh3a1, leading to reductive stress.
  • Discovered druggable E3s and DUBs (e.g., Herc2, Ubr4, Huwe1) as Keap1-dependent co-vulnerabilities.
  • Demonstrated that depleting these co-dependencies ablated in vivo tumor development in Keap1-inactivated models.

Conclusions:

  • KEAP1 inactivation can suppress tumor growth in a genetically defined subset of NSCLC through Nrf2/Aldh3a1 activation and reductive stress.
  • Targeting the UPS, specifically Keap1-dependent co-vulnerabilities like E3 ligases, presents a promising therapeutic strategy for KEAP1-mutated NSCLC.
  • The UPS is an underexplored therapeutic avenue for patients with KEAP1-inactivated tumors, particularly under metabolic stress conditions.
Keywords:
CRISPR/Cas9Keap1NSCLCReductive StressUbiquitin-Proteasome System

More Related Videos

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones11:36

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones

Published on: July 25, 2019

11.6K
Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations10:26

Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations

Published on: November 7, 2019

6.2K

Related Concept Videos

Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
9.9K
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
9.2K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
3.0K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
9.1K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
3.2K
The Proteasome01:13

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
2.0K