Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Lung adenocarcinoma (LUAD) often involves KEAP1 mutations, causing NRF2 pathway hyperactivation and poor prognosis.
• KEAP1 mutations accelerate KRAS-driven LUAD and create a dependency on glutaminolysis.
• Understanding genetic dependencies in KEAP1-mutant LUAD is crucial for identifying novel therapeutic strategies.

Purpose of the Study:

• To identify KEAP1 mutant-specific genetic dependencies in LUAD.
• To investigate the role of solute carrier family 33 member 1 (SLC33A1) in KEAP1-mutant LUAD.
• To validate SLC33A1 as a potential therapeutic target for KEAP1-mutant LUAD.

Main Methods:

• Druggable genome CRISPR-Cas9 screening in KEAP1-mutant LUAD cells.
• Targeted genetic and biochemical experiments in mouse and human LUAD models.
• Preclinical genetically-engineered mouse models (GEMMs) of LUAD.
• Unbiased genome-wide CRISPR screening.

Main Results:

• A significant KEAP1 mutant-specific dependency on SLC33A1 was identified.
• SLC33A1 and related genes in the unfolded protein response are critical.
• SLC33A1 was validated as a robust dependency in various KEAP1-mutant LUAD models.
• Additional genes related to SLC33A1 dependency were uncovered.

Conclusions:

• KEAP1-mutant LUAD exhibits a specific dependency on SLC33A1.
• Targeting SLC33A1 may be a viable therapeutic strategy for patients with KEAP1-mutant or NRF2-hyperactivated tumors.
• Integrating functional genetics and GEMMs is valuable for discovering genotype-specific therapeutic targets.