主要驱动癌基因 MYC、突变型 KRAS 和突变型 TP53 通常共存并协同促进人类肿瘤形成，从而在其下游分子程序中带来抗癌治疗机会。然而，关于癌基因之间的冗余和竞争是否影响其驱动肿瘤的程序和能力的研究很少。通过 CRISPR-Cas9 介导的下调，我们在肺癌、结肠癌和胰腺癌中的一组细胞系中评估了 MYC、突变型 KRAS 和突变型 TP53 的下游蛋白质组学和转录组学程序，其中这些癌基因中的一个或三个被激活。通过对常见激活的分子程序进行 RNAi 筛选，我们发现了三种蛋白质的特征 - RUVBL1、HSPA9 和 XPO1，这些蛋白质可以通过新药物组合有效地靶向所研究的癌症类型。有趣的是，该特征是由癌蛋白以冗余或竞争方式而不是合作方式控制的。每个癌蛋白单独上调靶基因，而在癌基因共表达时，每个靶标优选地由显性癌蛋白控制，从而减少其他癌蛋白的影响。这种相互作用是通过靶基因激活的冗余途径介导的（如突变型 KRAS 向 c-Jun/GLI2 转录因子发出信号绕过 c-Myc 激活的情况），以及通过竞争介导的（如突变型 p53 和 c-Myc 竞争的情况）用于结合目标启动子。来自细胞系和患者样本的全局转录组学数据表明，致癌程序的冗余和竞争是广泛的现象，甚至可能构成依赖癌蛋白的大部分基因，如结肠癌细胞系和肺癌细胞系中突变的 p53 所示。尽管如此，我们证明冗余的癌基因程序包含有效抗癌药物组合的目标，绕过了直接癌蛋白抑制的限制。© 2024。作者。

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.© 2024. The Author(s).