Targeting SLC7A11-induced nutrient dependency in cancer: mechanisms and preclinical translation

项目摘要 癌细胞中的特定遗传改变可能会重新编程其代谢网络，并使其高度依赖于癌症。 依赖特定的营养物质生存对癌症营养依赖性的机制性理解 细胞对癌症治疗具有重要意义，因为损害营养代谢的药物可能会 有效杀死依赖特定营养生存的癌细胞，同时保留正常细胞。而 靶向营养依赖已经在白血病中取得了成功，迄今为止， 靶向实体瘤中的营养依赖性。因此，非常需要了解 靶向癌细胞中营养依赖性的抗肿瘤剂的作用机制。SLC 7A 11是一种 一种氨基酸转运蛋白，能够使胱氨酸摄取并随后转化为半胱氨酸，这是至关重要的 以维持氧化还原平衡和细胞存活。SLC 7A 11经常在人类癌症中过表达， 包括KEAP 1突变型肺癌。本申请旨在确定的作用和机制， SLC 7A 11在调节营养物依赖性和治疗靶向癌症中的营养物依赖性中的作用 SLC 7A 11的异常表达。我们的具体目标是：具体目标1：确定代谢机制 潜在的SLC 7A 11诱导的癌细胞中的葡萄糖依赖性。具体目标2：确定治疗 抑制GLUT或PPP在治疗具有异常SLC 7A 11表达的肿瘤中的潜力。的理由 研究SLC 7A 11在调节葡萄糖依赖性中的作用不仅 推进我们对癌细胞营养依赖性的机械理解， 深入了解针对SLC 7A 11代谢脆弱性的新型治疗策略的发展- 过度表达肿瘤我们提出的研究将对我们理解 营养依赖的基本机制和我们治疗营养依赖的能力， 癌症治疗

Project Summary Specific genetic alterations in cancer cells may reprogram their metabolic networks and render them highly dependent on particular nutrients for survival. A mechanistic understanding of nutrient dependency in cancer cells has important implications for cancer treatment because drugs that impair nutrient metabolism may be effective for killing cancer cells that depend on specific nutrients for survival while sparing normal cells. While targeting nutrient dependency has been successful in leukemia, to date there has been limited success in targeting nutrient dependency in solid tumors. Therefore, there is a significant need to understand the mechanisms of action of anti-neoplastic agents that target nutrient dependency in cancer cells. SLC7A11 is an amino acid transporter that enables cystine uptake and its subsequent conversion to cysteine, which is critical for maintaining redox balance and cell survival. SLC7A11 is frequently overexpressed in human cancers, including KEAP1-mutant lung cancers. This application aims to determine the roles and mechanisms of SLC7A11 in regulating nutrient dependency and to therapeutically target nutrient dependency in cancers with aberrant expression of SLC7A11. Our specific aims are: Specific Aim 1: To determine the metabolic mechanisms underlying SLC7A11-induced glucose dependency in cancer cells. Specific Aim 2: To determine the therapeutic potential of inhibiting GLUTs or the PPP in treating tumors with aberrant SLC7A11 expression. The rationale for the proposed research is that studying the roles of SLC7A11 in regulating glucose dependency will not only advance our mechanistic understanding of nutrient dependency in cancer cells but also provide important insights into the development of novel therapeutic strategies to target metabolic vulnerabilities in SLC7A11- overexpressing tumors. Our proposed studies will have significant impact on both our understanding of the fundamental mechanisms of nutrient dependency and our ability to therapeutically target nutrient dependency in cancer treatment.