背景:体细胞拷贝数改变是癌症的标志,为治疗开发提供了独特的机会。这里,我们专注于确定携带染色体8p缺失的肿瘤的特定漏洞。
方法:我们开发并应用了癌症基因组图谱(TCGA)的综合分析,癌症依存关系图(DepMap),和癌细胞系百科全书,以确定染色体8p特异性漏洞。我们采用正交基因靶向策略,在体外和体内,包括短发夹RNA介导的基因敲除和CRISPR/Cas9介导的基因敲除以验证漏洞。
结果:我们确定了SLC25A28(也称为MFRN2),作为携带染色体8p缺失的肿瘤的特殊脆弱性。我们证明了对MFRN2损失的脆弱性是由其模拟物的表达决定的,SLC25A37(也称为MFRN1),位于染色体8p上。根据它们作为线粒体铁转运蛋白的功能,MFRN1/2旁系同源蛋白缺乏严重损害线粒体呼吸,诱导铁-硫簇蛋白的全球消耗,导致DNA损伤和细胞死亡.MFRN2在缺乏MFRN1的肿瘤中的消耗导致生长受损,甚至在临床前小鼠异种移植实验中肿瘤根除,突出其治疗潜力。
结论:我们的数据揭示了MFRN2作为8p染色体缺失癌症的治疗靶标,并将MFNR1作为MFRN2定向治疗的补充生物标志物。
Somatic copy number alterations are a hallmark of cancer that offer unique opportunities for therapeutic exploitation. Here, we focused on the identification of specific vulnerabilities for tumors harboring chromosome 8p deletions.
We developed and applied an integrative analysis of The Cancer Genome Atlas (TCGA), the Cancer Dependency Map (DepMap), and the Cancer Cell Line Encyclopedia to identify chromosome 8p-specific vulnerabilities. We employ orthogonal gene targeting strategies, both in vitro and in vivo, including short hairpin RNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout to validate vulnerabilities.
We identified SLC25A28 (also known as MFRN2), as a specific vulnerability for tumors harboring chromosome 8p deletions. We demonstrate that vulnerability towards MFRN2 loss is dictated by the expression of its paralog, SLC25A37 (also known as MFRN1), which resides on chromosome 8p. In line with their function as mitochondrial iron transporters, MFRN1/2 paralog protein deficiency profoundly impaired mitochondrial respiration, induced global depletion of iron-sulfur cluster proteins, and resulted in DNA-damage and cell death. MFRN2 depletion in MFRN1-deficient tumors led to impaired growth and even tumor eradication in preclinical mouse xenograft experiments, highlighting its therapeutic potential.
Our data reveal MFRN2 as a therapeutic target of chromosome 8p deleted cancers and nominate MFNR1 as the complimentary biomarker for MFRN2-directed therapies.