Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Lung cancer is a leading cause of cancer mortality with limited effective therapies for many patients.
• Genomic studies reveal frequent alterations in SWI/SNF chromatin remodeling complex genes, including SMARCA4 and ARID1A.
• Understanding SWI/SNF mutations is crucial for developing novel lung cancer treatment approaches.

Purpose of the Study:

• To investigate the role of SMARCA4 in lung adenocarcinoma tumorigenesis.
• To identify therapeutic vulnerabilities associated with SMARCA4 loss in lung cancer.
• To explore the potential of targeting oxidative phosphorylation (OXPHOS) in SWI/SNF-mutant lung tumors.

Main Methods:

• Development of a genetically engineered mouse model ablating Smarca4 in lung epithelium.
• Gene expression analysis to identify metabolic signatures in SMARCA4-mutant tumors.
• Assessment of cellular oxygen consumption and respiratory capacity.
• Evaluation of sensitivity to OXPHOS inhibition using IACS-010759 in cell lines and xenografts.

Main Results:

• Smarca4 functions as a tumor suppressor, cooperating with p53 loss and Kras activation.
• SMARCA4-mutant lung tumors exhibit a signature of enhanced oxidative phosphorylation (OXPHOS).
• SMARCA4-deficient cells show increased oxygen consumption and respiratory capacity.
• SMARCA4-mutant lung cancer is sensitive to OXPHOS inhibition by IACS-010759.
• SMARCA4-deficient cells display a blunted response to energy stress, indicating synthetic lethality.

Conclusions:

• SMARCA4 loss in lung cancer creates a dependency on OXPHOS.
• Targeting OXPHOS represents a promising therapeutic strategy for SWI/SNF-mutant lung cancers.
• This study provides a mechanistic rationale for developing OXPHOS inhibitors as cancer therapeutics.