Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer

Area of Science:

• Oncology
• Metabolic pathways
• Cancer genetics

Background:

• Non-small-cell lung cancer (NSCLC) with concurrent KRAS and LKB1 mutations (KL NSCLC) is aggressive and treatment-resistant.
• This subtype presents significant challenges in clinical management due to poor therapeutic outcomes.
• Understanding the underlying molecular mechanisms is crucial for developing novel treatment strategies.

Purpose of the Study:

• To identify metabolic vulnerabilities in KL NSCLC.
• To elucidate the role of serine-glycine-one-carbon (SGOC) metabolism in this cancer subtype.
• To explore potential therapeutic targets based on metabolic dysregulation.

Main Methods:

• Analysis of RNA-seq and metabolomics data from human NSCLC samples.
• Investigation of the salt-induced kinase (SIK)-NRF2 signaling pathway.
• Utilizing chemical and genetic inhibition of serine hydroxymethyltransferase (SHMT).
• In vivo therapeutic efficacy studies in mouse models.

Main Results:

• LKB1 loss enhances SGOC metabolism by upregulating SHMT, particularly in conjunction with KEAP1 loss.
• The SIK-NRF2 axis is inactivated, leading to SHMT activation and increased one-carbon unit supply for antioxidant defense.
• Suppression of SHMT increases sensitivity to oxidative stress and cell death.
• SHMT inhibition potentiates paclitaxel efficacy in KEAP1-mutant KL tumors.

Conclusions:

• KL NSCLC exhibits a metabolic dependency on SGOC metabolism regulated by SHMT.
• Targeting SHMT represents a promising therapeutic strategy for KL NSCLC, especially when combined with therapies inducing oxidative stress.
• This research provides critical insights into the metabolic adaptations of aggressive NSCLC and suggests new avenues for treatment.