PO.ET02.12 · 实验与分子治疗

SLC25A28 是核苷酸切除修复缺陷型癌症中的合成致死靶点

SLC25A28 is a synthetic lethal target in nucleotide excision repair-deficient cancer

编号 3093 展板 21 时间 4/20 02:00–05:00 区域 Section 16 主讲 Nan Yang, PhD

分会场 Novel Therapeutics and Drug Targets 2

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作者与单位 Authors & Affiliations

Nan Yang¹, Vijai Joseph¹, Lisa Hoeg², Xuechun Bai¹, Sizhi Gao¹, Ouathek Ouerfelli¹, David B. Solit¹, Jian Carrot-Zhang¹, Gopa Iyer¹, Daniel Durocher², Kent W. Mouw³, Kenneth Offit¹, Steven M. Lipkin⁴

¹Memorial Sloan Kettering Cancer Center, New York, NY,²Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada,³Radiation Oncology, Dana Farber Cancer Institute, Boston, MA,⁴Weill Cornell Medical College, New York, NY

摘要 Abstract

中文摘要

背景：核苷酸切除修复缺陷型（NER-D）癌症约占膀胱尿路癌和子宫癌的 10%。铂类化疗是 NER-D 癌症当前的标准治疗方案；然而其肾毒性限制了其在肾功能受损患者中的适用性。目前尚未鉴定出针对 NER-D 肿瘤的可成药靶点。全基因组 CRISPR 筛选提供了一种强有力的策略来鉴定合成致死相互作用。我们进行了全基因组筛选，以鉴定 NER 缺陷细胞中潜在的合成致死靶点。方法：构建了 RT112/84 ERCC4 敲除（ERCC4-/-）细胞系。通过 Sanger 测序和 Western 印迹检测 ERCC4 状态，并使用宿主细胞再激活实验（HCRA）评估核苷酸切除修复活性。在 RT112/84 野生型（WT）和 ERCC4-/- 细胞中进行全基因组 CRISPR 筛选，以鉴定候选合成致死靶点。集落形成实验验证候选相互作用，并进一步检验 SLC25A28 与 ERCC2、ERCC3 和 ERCC5 的合成致死性。进行 RNA 测序以探究 SLC25A28-ERCC4 合成致死性的潜在机制。结果：Sanger 测序和 Western 印迹证实了 RT112/84 细胞中的 ERCC4 敲除。HCRA 显示 ERCC4-/- 细胞中 NER 活性显著降低。全基因组 CRISPR 筛选鉴定出 SLC25A28 是与 ERCC4 合成致死的顶级候选。集落实验验证了 SLC25A28 与 ERCC2、ERCC3、ERCC4 和 ERCC5 之间的合成致死性。结论：我们的发现鉴定 SLC25A28 是 NER 缺陷型癌症中一个新型合成致死靶点，提示抑制 SLC25A28 可能代表针对携带 NER 通路突变肿瘤的潜在治疗策略。本研究由 STTR 1 R41 CA275627-01、Niehaus 遗传性癌症基因组学中心以及乳腺癌研究基金会资助。

查看英文原文 English abstract

Background: Nucleotide excision repair-deficient (NER-D) cancers comprise approximately 10% of bladder urinary tract and uterine cancers. Platinum-based chemotherapy is the current standard of care for NER-D cancers; however, its nephrotoxicity limits applicability in patients with compromised renal function. No druggable targets have been identified for NER-D tumors. Genome-wide CRISPR screening offers a powerful strategy to identify synthetic lethal interactions. We performed a genome-wide screen to identify potential synthetic lethal targets in NER-deficient cells. Methods: An RT112/84 ERCC4 knockout ( ERCC4 -/- ) cell line was generated. ERCC4 status was examined by Sanger sequencing and Western blotting, and nucleotide excision repair activity was assessed using the Host Cell Reactivation Assay (HCRA). A genome-wide CRISPR screen was performed in RT112/84 wild-type (WT) and ERCC4 -/- cells to identify candidate synthetic lethal targets. Colony formation assays validated candidate interactions, and SLC25A28 was further tested for synthetic lethality with ERCC2 , ERCC3 , and ERCC5 . RNA sequencing was conducted to investigate the mechanism underlying SLC25A28-ERCC4 synthetic lethality. Results: Sanger sequencing and Western blot confirmed ERCC4 knockout in RT112/84 cells. HCRA demonstrated markedly reduced NER activity in ERCC4 -/- cells. Genome-wide CRISPR screening identified SLC25A28 as a top synthetic lethal candidate with ERCC4 . Colony assays validated the synthetic lethality between SLC25A28 and ERCC2 , ERCC3 , ERCC4 and ERCC5 . Conclusions: Our findings identify SLC25A28 as a novel synthetic lethal target in NER-deficient cancers, suggesting that inhibition of SLC25A28 may represent a potential therapeutic strategy for tumors harboring NER pathway mutations. This study was supported by STTR 1 R41 CA275627-01, the Niehaus Center for Inherited Cancer Genomics, and the Breast Cancer Research Foundation.

利益披露 Disclosure

N. Yang, None.. V. Joseph, None.. L. Hoeg, None.. X. Bai, None.. S. Gao, None.. O. Ouerfelli, None.. J. Carrot-Zhang, None.. G. Iyer, None.. K. W. Mouw, None.. S. M. Lipkin, None.

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