Mitoferrin2 is a synthetic lethal target for chromosome 8p deleted cancers

Area of Science:

• Oncology
• Cancer Genomics
• Molecular Biology

Background:

• Somatic copy number alterations are key cancer features with therapeutic potential.
• Chromosome 8p deletions present specific vulnerabilities in cancer.

Purpose of the Study:

• To identify vulnerabilities specific to tumors with chromosome 8p deletions.
• To explore the therapeutic potential of targeting these vulnerabilities.

Main Methods:

• Integrative analysis of TCGA, DepMap, and CCLE datasets.
• In vitro and in vivo validation using gene knockdown and knockout strategies.
• Orthogonal gene targeting including shRNA and CRISPR/Cas9.

Main Results:

• SLC25A28 (MFRN2) identified as a vulnerability in chromosome 8p-deleted tumors.
• MFRN2 vulnerability is dependent on the expression of its paralog, SLC25A37 (MFRN1).
• MFRN1/2 deficiency impairs mitochondrial respiration, iron-sulfur cluster proteins, and induces DNA damage, leading to cell death. MFRN2 targeting eradicated tumors in mouse models.

Conclusions:

• MFRN2 is a therapeutic target for chromosome 8p deleted cancers.
• MFRN1 serves as a predictive biomarker for MFRN2-directed therapies.