人们对KRAS癌基因如何驱动癌症生长仍然知之甚少。研究人员建立了KRAS突变癌症中KRAS和细胞外信号调节激酶（ERK）依赖基因转录的全系统图谱，以描述生长和抑制剂耐药性的分子机制。意想不到的是，KRAS依赖性基因特征与经常被引用的标志性KRAS信号基因特征有很大不同，它主要通过ERK丝裂原活化蛋白激酶（MAPK）级联驱动，并准确反映了KRAS突变癌症患者中KRAS和ERK调节的基因转录。
与ERK调控磷酸化和总蛋白组相结合，突出显示了ERK对后期促进复合体/细胞周期体（APC/C）和细胞周期机制其他成分的调控失调，是驱动胰腺导管腺癌（PDAC）生长的关键过程。这些研究结果从机理上阐明了，ERK在驱动KRAS突变肿瘤生长和KRAS-ERK MAPK靶向疗法耐药中的关键作用。
附：英文原文
Title: Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers
Author: Jeffrey A. Klomp, Jennifer E. Klomp, Clint A. Stalnecker, Kirsten L. Bryant, A. Cole Edwards, Kristina Drizyte-Miller, Priya S. Hibshman, J. Nathaniel Diehl, Ye S. Lee, Alexis J. Morales, Khalilah E. Taylor, Sen Peng, Nhan L. Tran, Laura E. Herring, Alex W. Prevatte, Natalie K. Barker, Laura D. Hover, Jill Hallin, Saikat Chowdhury, Oluwadara Coker, Hey Min Lee, Craig M. Goodwin, Prson Gautam, Peter Olson, James G. Christensen, John P. Shen, Scott Kopetz, Lee M. Graves, Kian-Huat Lim, Andrea Wang-Gillam, Krister Wennerberg, Adrienne D. Cox, Channing J. Der
Issue&Volume: 2024-06-07
Abstract: How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal–regulated kinase (ERK)–dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.
DOI: adk0775
Source: https://www.science.org/doi/10.1126/science.adk0775