Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
Proc Natl Acad Sci U S A. 2023 Feb 7;120(6):e2212072120. doi: 10.1073/pnas.2212072120. Epub 2023 Feb 1.
Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, possibly due to alternative metabolic pathways that counteract the most damaging effects. To identify such alternative pathways, we screened for metabolic pathways exhibiting synthetic lethality with inhibition of the DNA damage response kinase Ataxia-telangiectasia-mutated (ATM) using a metabolism-centered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 library. Our data revealed Kelch-like ECH-associated protein 1 (KEAP1) as a key factor involved in desensitizing cancer cells to ATM inhibition both in vitro and in vivo. Cells depleted of KEAP1 exhibited an aberrant overexpression of the cystine transporter SLC7A11, robustly accumulated cystine inducing disulfide stress, and became hypersensitive to ATM inhibition. These hallmarks were reversed in a reducing cellular environment indicating that disulfide stress was a crucial factor. In The Cancer Genome Atlas (TCGA) pan-cancer datasets, we found that ATM levels negatively correlated with KEAP1 levels across multiple solid malignancies. Together, our results unveil ATM and KEAP1 as new targetable vulnerabilities in solid tumors.
针对 DNA 修复缺陷的癌症治疗方法常常会遇到耐药性，这可能是由于替代代谢途径抵消了最具破坏性的影响。为了鉴定这种替代途径，我们使用以代谢为中心的成簇规律间隔短回文重复序列（CRISPR）/ Cas9 文库筛选出与 DNA 损伤反应激酶共济失调毛细血管扩张突变（ATM）抑制作用具有合成致死性的代谢途径。我们的数据表明 Kelch 样 ECH 相关蛋白 1（KEAP1）是使癌细胞对 ATM 抑制作用脱敏的关键因素，无论是在体外还是体内。耗尽 KEAP1 的细胞表现出胱氨酸转运蛋白 SLC7A11 的异常过表达，强烈积累胱氨酸诱导的二硫键应激，并对 ATM 抑制作用变得高度敏感。这些特征在还原细胞环境中得到逆转，表明二硫键应激是一个关键因素。在癌症基因组图谱（TCGA）泛癌症数据集，我们发现 ATM 水平与多个实体恶性肿瘤中的 KEAP1 水平呈负相关。总之，我们的研究结果揭示了 ATM 和 KEAP1 是实体肿瘤中可靶向的新弱点。
