In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1 -mutant lung cancer.
In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1 -mutant lung cancer.
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体内代谢组学将 CD38 确定为 LKB1 突变型肺癌中的一个新的脆弱性。
DOI：
10.1101/2023.04.18.537350
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Dowling,C
中科院分区：
文献类型：
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作者：
Deng,Jiehui;Peng,DavidH;Fenyo,David;Yuan,Hao;Lopez,Alfonso;Levin,DanielS;Meynardie,Mary;Quinteros,Mari;Ranieri,Michela;Sahu,Soumyadip;Lau,SallyCM;Shum,Elaine;Velcheti,Vamsidhar;Punekar,SalmanR;Rekhtman,Natasha;Dowling,C
LKB1/STK11 是一种丝氨酸/苏氨酸激酶，在控制细胞代谢中发挥重要作用，导致 LKB1 突变癌症的潜在治疗漏洞。在这里，我们将 NAD+ 降解胞外酶 CD38 确定为 LKB1 突变 NSCLC 的新靶点。基因工程小鼠模型 (GEMM) 的代谢谱显示，LKB1 突变型肺癌的 ADP-核糖（关键氧化还原辅因子 NAD+ 的分解产物）显着增加。令人惊讶的是，与其他遗传亚群相比，小鼠和人类 LKB1 突变 NSCLC 在肿瘤细胞表面显示出 NAD+ 分解代谢胞外酶 CD38 的显着过度表达。 LKB1 缺失或盐诱导激酶 (SIK)（LKB1 的关键下游效应子）失活可通过 CD38 启动子中的 CREB 结合位点诱导 CD38 转录诱导。使用 FDA 批准的抗 CD38 抗体 daratumumab 进行治疗可抑制 LKB1 突变 NSCLC 异种移植物的生长。总之，这些结果表明 CD38 作为 LKB1 突变型肺癌患者的一个有前途的治疗靶点。 意义 肺腺癌患者的 LKB1 肿瘤抑制因子的功能丧失突变与对当前治疗的耐药性相关。我们的研究发现 CD38 是一个潜在的治疗靶点，在这种特定的癌症亚型中高度过度表达，与 NAD 稳态的变化相关。
LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD+degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD+. Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)—key downstream effectors of LKB1— induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer.SIGNIFICANCELoss-of-function mutations in theLKB1tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.