癌症中癌基因c-Myc、突变KRAS和突变p53的共同药物靶向签名揭示了癌基因之间的功能冗余和竞争关系

A common druggable signature of oncogenic c-Myc, mutant KRAS and mutant p53 reveals functional redundancy and competition among oncogenes in cancer

Cell Death & Disease

影响因子:9.6

分区:生物学1区 Top / 细胞生物学2区

发表日期:2024 Aug 31

作者: Maria Grześ, Akanksha Jaiswar, Marcin Grochowski, Weronika Wojtyś, Wojciech Kaźmierczak, Tomasz Olesiński, Małgorzata Lenarcik, Magdalena Nowak-Niezgoda, Małgorzata Kołos, Giulia Canarutto, Silvano Piazza, Jacek R Wiśniewski, Dawid Walerych

DOI: 10.1038/s41419-024-06965-3

摘要

主要驱动癌基因MYC、突变KRAS和突变TP53通常共存并协作促进人体肿瘤发生，从而在其下游分子程序中带来抗癌治疗的潜在机会。然而，目前关于癌基因之间的冗余和竞争是否影响其程序及驱动肿瘤的能力的研究较少。通过CRISPR-Cas9介导的下调，我们评估了在肺癌、结肠癌和胰腺癌的一组细胞系中，激活或未激活一个或三个这些癌基因后，其下游蛋白组学和转录组学程序。利用RNA干扰筛查常激活的分子程序，发现了由三种蛋白组成的签名—RUVBL1、HSPA9和XPO1，这些蛋白可以通过新颖的药物组合高效靶向所研究的癌症类型。有趣的是，该签名由癌基因以冗余或竞争的方式调控，而非合作。每个癌基因单独上调目标基因，但在共同表达时，目标由占优势的癌基因控制，从而减弱其他癌基因的影响。这一相互作用通过目标基因激活的冗余路径（如突变KRAS信号绕过c-Myc激活而直接作用于c-Jun/GLI2转录因子）以及竞争（如突变p53与c-Myc在靶基因启动子上的结合竞争）得以实现。来自细胞系和患者样本的全转录组数据表明，癌基因程序的冗余和竞争是广泛存在的现象，甚至可能占据大多数依赖于癌基因调控的基因，正如在结肠癌和肺癌细胞系中突变p53所示。尽管如此，我们证明了冗余的癌基因程序中含有可被高效抗癌药物组合靶向的目标，从而突破了直接抑制癌基因的局限。

Abstract

The major driver oncogenes MYC, mutant KRAS, and mutant TP53 often coexist and cooperate to promote human neoplasia, which results in anticancer therapeutic opportunities within their downstream molecular programs. However, little research has been conducted on whether redundancy and competition among oncogenes affect their programs and ability to drive neoplasia. By CRISPR‒Cas9-mediated downregulation we evaluated the downstream proteomics and transcriptomics programs of MYC, mutant KRAS, and mutant TP53 in a panel of cell lines with either one or three of these oncogenes activated, in cancers of the lung, colon and pancreas. Using RNAi screening of the commonly activated molecular programs, we found a signature of three proteins - RUVBL1, HSPA9, and XPO1, which could be efficiently targeted by novel drug combinations in the studied cancer types. Interestingly, the signature was controlled by the oncoproteins in a redundant or competitive manner rather than by cooperation. Each oncoprotein individually upregulated the target genes, while upon oncogene co-expression each target was controlled preferably by a dominant oncoprotein which reduced the influence of the others. This interplay was mediated by redundant routes of target gene activation - as in the case of mutant KRAS signaling to c-Jun/GLI2 transcription factors bypassing c-Myc activation, and by competition - as in the case of mutant p53 and c-Myc competing for binding to target promoters. The global transcriptomics data from the cell lines and patient samples indicate that the redundancy and competition of oncogenic programs are broad phenomena, that may constitute even a majority of the genes dependent on oncoproteins, as shown for mutant p53 in colon and lung cancer cell lines. Nevertheless, we demonstrated that redundant oncogene programs harbor targets for efficient anticancer drug combinations, bypassing the limitations for direct oncoprotein inhibition.