Validating novel synthetically lethal vulnerabilities in lung cancer

验证肺癌中新的综合致命弱点

• 批准号: 2619070
• 金额: --
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2619070
• 关键词: Validating; novel; synthetically; lethal; vulnerabilities

"LIMD1 (LIM domains containing 1) is a tumour suppressor gene frequently lost during the early stages of non-small cell lung cancer (NSCLC), resulting in a worse outcome for LIMD1-deficient patients.LIMD1 deficiency is present in approximately fifty percent of NSCLC cases, representing at least 21,000 patients in the United Kingdom and 1.2 million worldwide. Our lab, in collaboration with the CRUK Functional Genomic Centre, conducted a whole genome CRISPR-Cas9 functional genomic screen to identify novel vulnerabilities in LIMD1-deficient lung cancer cells in order to develop personalised treatments for this subset of NSCLC patients.In LIMD1-deficient cells, the screen revealed a significant enrichment of genes involved in selenocysteinyl-tRNA biosynthesis and selenocysteine incorporation as novel dependencies. Notably, the only enzyme identified to contain selenocysteine was GPX4, which detoxifies lipid peroxides and protects cells from ferroptosis. We therefore hypothesise that early LIMD1 loss may influence lung cancer cell sensitivity or resistance to ferroptosis.Our goals include validating GPX4 as a novel vulnerability in LIMD1-deficient lung cancer cells, assessing sensitivity or resistance to ferroptosis in a larger panel of lung cancer cell lines, and elucidating the mechanisms that regulate sensitivity or resistance to ferroptosis in LIMD1-deficient cells. Using a siRNA-mediated method to reduce GPX4 levels, our findings indicate that LIMD1-deficient cells are more sensitive than LIMD1-proficient cells. In addition, when treated with ferroptosis-inducing compounds RSL3 and erastin, LIMD1-deficient cells were more sensitive than LIMD1-sufficient cells.Our lab is exploring the unrealised potential of LIMD1 in the biology of lung cancer, and we hope this will lead to revolutionary advances in targeted cancer treatments for a significant subset of patients."

LIMD 1（LIM domains containing 1）是一种肿瘤抑制基因，在非小细胞肺癌（NSCLC）的早期阶段经常丢失，导致LIMD 1缺陷患者的预后更差。LIMD 1缺陷存在于大约50%的NSCLC病例中，代表英国至少21，000例患者和全球120万例患者。我们的实验室与CRUK Functional Genomic Centre合作，进行了一项全基因组CRISPR-Cas9功能基因组筛选，以识别LIMD 1缺陷型肺癌细胞中的新漏洞，从而为这一亚群NSCLC患者开发个性化治疗。在LIMD 1缺陷型细胞中，筛选发现参与硒代半胱氨酸-tRNA生物合成和硒代半胱氨酸掺入的基因显著富集，作为新的依赖性。值得注意的是，唯一被鉴定含有硒代半胱氨酸的酶是GPX 4，它可以解毒脂质过氧化物并保护细胞免受铁凋亡。因此，我们假设，早期LIMD 1的损失可能会影响肺癌细胞的敏感性或抵抗ferroptosis。我们的目标包括验证GPX 4作为一种新的弱点在LIMD 1缺陷的肺癌细胞，评估的敏感性或抵抗ferroptosis在一个更大的面板的肺癌细胞系，并阐明调节的机制，在LIMD 1缺陷的细胞的敏感性或抵抗ferroptosis。使用siRNA介导的方法来降低GPX 4水平，我们的研究结果表明，LIMD 1缺陷细胞比LIMD 1精通细胞更敏感。此外，当用铁凋亡诱导化合物RSL 3和erastin治疗时，LIMD 1缺陷细胞比LIMD 1充足的细胞更敏感。我们的实验室正在探索LIMD 1在肺癌生物学中未实现的潜力，我们希望这将导致针对重要患者亚群的靶向癌症治疗的革命性进展。"