致癌C-Myc，突变体KRAS和突变体p53的常见可药物特征揭示了癌症中癌基因的功能冗余和竞争
A common druggable signature of oncogenic c-Myc, mutant KRAS and mutant p53 reveals functional redundancy and competition among oncogenes in cancer
影响因子:9.60000
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
摘要
主要的驱动器癌基因MYC，突变体KRAS和突变体TP53经常共存并合作以促进人类肿瘤，这在其下游分子程序中导致抗癌治疗机会。但是，关于癌基因之间的冗余和竞争是否会影响其计划和驱动肿瘤的能力，进行了很少的研究。通过CRISPR = CAS9介导的下调，我们评估了MYC，Mutant KRAS和突变体TP53的下游蛋白质组学和转录组学计划，在肺，结肠和胰腺的癌症中激活了其中一个或三个癌基因的细胞系。使用常见活化分子程序的RNAi筛选，我们发现了三种蛋白质的特征 - RUVBL1，HSPA9和XPO1，可以通过研究癌症类型中的新药物组合有效地靶向。有趣的是，该签名是由多余或竞争方式而不是通过合作控制的癌蛋白控制的。每种癌蛋白分别上调了靶基因，而在癌基因共表达后，每个靶标优选地通过主要的癌蛋白来控制，从而降低了其他靶基蛋白。该相互作用是由靶基因激活的冗余途径介导的 - 与突变的KRAS信号传导绕过C-JUN/GLI2转录因子绕过C-MYC激活，以及竞争 - 在突变p53和C-Myc的情况下，竞争与目标启动子的结合。来自细胞系和患者样品的全球转录组学数据表明，致癌程序的冗余和竞争是广泛的现象，甚至可能构成大多数基因依赖癌蛋白，如结肠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计划具有有效的抗癌药物组合的目标，绕开了直接癌蛋白抑制的局限性。
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.