Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Concurrent loss-of-function mutations in STK11 and KEAP1 are linked to aggressive lung adenocarcinoma (LUAD), characterized by rapid tumor growth, therapeutic resistance, and poor prognosis.
• Understanding the molecular mechanisms underlying STK11/KEAP1 co-mutation is crucial for developing effective treatments for this aggressive LUAD subtype.

Purpose of the Study:

• To investigate the functional consequences of combined STK11 and KEAP1 loss in LUAD.
• To identify specific molecular vulnerabilities associated with STK11/KEAP1 co-mutations.
• To evaluate the therapeutic potential of targeting identified vulnerabilities in STK11/KEAP1 co-mutant LUAD.

Main Methods:

• Comparison of LUAD models with co-mutant, single-mutant, and wild-type STK11/KEAP1.
• Analysis of gene expression, focusing on ferroptosis-protective genes.
• CRISPR screening to identify essential genes in co-mutant LUAD.
• Genetic and pharmacological inhibition of candidate genes.

Main Results:

• STK11/KEAP1 co-mutation significantly upregulates ferroptosis-protective genes, including stearoyl-CoA desaturase (SCD) and aldo-keto reductase family 1 members (AKR1C1/2/3).
• Co-mutant LUAD exhibits resistance to ferroptosis induction.
• CRISPR screening identified SCD (specifically SCD1) as selectively essential in STK11/KEAP1 co-mutant LUAD.
• Inhibition of SCD1 enhances the efficacy of ferroptosis-inducing agents.

Conclusions:

• STK11/KEAP1 co-mutation confers resistance to ferroptosis through elevated expression of protective genes.
• SCD1 is a selective vulnerability in STK11/KEAP1 co-mutant LUAD.
• Targeting SCD1 represents a promising therapeutic strategy for patients with STK11/KEAP1 co-mutant lung adenocarcinoma.