De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.
De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.
复制标题
嘌呤从头代谢是 p16 表达低的癌症的代谢脆弱性。
DOI：
10.1101/2023.07.15.549149
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Chandran,U
中科院分区：
文献类型：
--
作者：
Tangudu,NaveenKumar;Buj,Raquel;Wang,Hui;Wang,Jiefei;Cole,AidanR;Uboveja,Apoorva;Fang,Richard;Amalric,Amandine;Sajjakulnukit,Peter;Lyons,MaureenA;Cooper,Kristine;Hempel,Nadine;Snyder,NathanielW;Lyssiotis,CostasA;Chandran,U
p16是由CDKN 2A基因编码的肿瘤抑制因子，其表达在大约50%的人类癌症中丢失。在其典型作用中，p16通过抑制细胞周期蛋白依赖性激酶来抑制G1-S期细胞周期进程。有趣的是，p16在代谢重编程中也有作用，我们以前发表过p16的缺失通过磷酸戊糖途径促进核苷酸合成。然而，p16/CDKN 2Aloss对其他核苷酸代谢途径和潜在治疗靶点的更广泛影响仍未被探索。在等基因人类和小鼠黑色素瘤细胞系中使用CRISPR敲除文库，我们确定了p16/CDKN 2A缺失的细胞存活所必需的几个核苷酸代谢基因。一致地，这些基因中的许多在具有p16敲低或内源性低CDKN 2A表达的黑素瘤细胞中上调。我们确定p16/CDKN 2A低表达的细胞对包括抗叶酸剂在内的多种新生嘌呤合成抑制剂敏感。最后，p16基因敲减的肿瘤对体内叶酸代谢抑制剂比对照组更敏感。总之，我们的数据提供了证据，重新评估这些药物在p16/CDKN 2A低肿瘤患者中的效用，因为p16/CDKN 2A的缺失可能为这些药物提供了一个治疗窗口。我们的数据表明，p16的丢失提供了一个治疗窗口，以杀死癌细胞与广泛使用的抗叶酸剂相对较小的毒性。
p16 is a tumor suppressor encoded by theCDKN2Agene whose expression is lost in approximately 50% of all human cancers. In its canonical role, p16 inhibits the G1–S-phase cell cycle progression through suppression of cyclin-dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. However, the broader impact of p16/CDKN2Aloss on other nucleotide metabolic pathways and potential therapeutic targets remains unexplored. Using CRISPR knockout libraries in isogenic human and mouse melanoma cell lines, we determined several nucleotide metabolism genes essential for the survival of cells with loss of p16/CDKN2A. Consistently, many of these genes are upregulated in melanoma cells with p16 knockdown or endogenously lowCDKN2Aexpression. We determined that cells with low p16/CDKN2Aexpression are sensitive to multiple inhibitors ofde novopurine synthesis, including antifolates. Finally, tumors with p16 knockdown were more sensitive to the antifolate methotrexatein vivothan control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2Alowtumors as loss of p16/CDKN2Amay provide a therapeutic window for these agents.SignificanceAntimetabolites were the first chemotherapies, yet many have failed in the clinic due to toxicity and poor patient selection. Our data suggest that p16 loss provides a therapeutic window to kill cancer cells with widely-used antifolates with relatively little toxicity.