Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance.
Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance.
复制标题
DOI：
10.3390/cancers13205126
复制
发表时间：
2021-10-13
期刊：
影响因子：
5.2
通讯作者：
Eibl G
中科院分区：
文献类型：
--
作者：
Rozengurt E;Eibl G
胰腺导管腺癌（PDAC）是胰腺癌最常见的形式，仍然是最致命的疾病之一。目前的证据，在这篇文章中讨论，暗示癌基因KRAS，转录共激活因子YES 1相关蛋白（雅普）和Src家族激酶（SFK）的原癌基因之间的相互作用在PDAC的发病机制，因此，他们代表潜在的治疗干预的目标。在这里，我们重点关注最近的机制和翻译研究，这些研究确定了PDAC启动和维持中KRAS、雅普和SFK之间的复杂串扰。此外，我们还讨论了针对这些关键信号节点和反馈回路的策略，特别考虑到防止耐药性的发展。胰腺导管腺癌（PDAC）是胰腺癌的主要形式，仍然是一种毁灭性的疾病。这篇综述的目的是强调最近的文献机制和翻译的发展，推进我们的理解之间的复杂串扰KRAS，雅普和Src酪氨酸激酶家族（SFK）在PDAC的发展和维护。我们讨论了最近的研究表明RAS二聚化在信号转导中的重要性和新的发现表明，SFK的有效的原癌成员磷酸化和抑制RAS功能。这些令人惊讶的发现意味着RAS在维持PDAC的某些亚型中可能不起关键作用。为了支持这一解释，目前的证据表明，PDAC的基底样亚型的生存较少依赖于RAS，但至少部分依赖于雅普/TAZ的活性。基于目前的证据，我们提出SFK促使PDAC细胞进入高转移、上皮-间充质转化（EMT）和对KRAS信号传导依赖性降低的状态，这是PDAC的侵袭性基底样/鳞状亚型的显著特征。PDAC治疗策略应考虑酪氨酸磷酸化对KRAS和SFK/雅普的相反作用，以设计靶向这些新的串扰机制并克服耐药性的药物组合。
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the most lethal diseases. Current evidence, discussed in this article, implicates an interplay between the oncogene KRAS, the transcriptional co-activator YES1-Associated Protein (YAP) and the proto-oncogenes of the Src family kinases (SFK) in the pathogenesis of PDAC and consequently, they represent potential targets for therapeutic intervention. Here, we focus on recent mechanistic and translational studies that identify a complex crosstalk between KRAS, YAP and SFK in PDAC initiation and maintenance. Additionally, we discuss strategies for targeting these crucial signaling nodes and the feedback loops emanating from them, with especial consideration to preventing the development of drug resistance. Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a devastating disease. The purpose of this review is to highlight recent literature on mechanistic and translational developments that advance our understanding of a complex crosstalk between KRAS, YAP and Src tyrosine kinase family (SFK) in PDAC development and maintenance. We discuss recent studies indicating the importance of RAS dimerization in signal transduction and new findings showing that the potent pro-oncogenic members of the SFK phosphorylate and inhibit RAS function. These surprising findings imply that RAS may not play a crucial role in maintaining certain subtypes of PDAC. In support of this interpretation, current evidence indicates that the survival of the basal-like subtype of PDAC is less dependent on RAS but relies, at least in part, on the activity of YAP/TAZ. Based on current evidence, we propose that SFK propels PDAC cells to a state of high metastasis, epithelial-mesenchymal transition (EMT) and reduced dependence on KRAS signaling, salient features of the aggressive basal-like/squamous subtype of PDAC. Strategies for PDAC treatment should consider the opposite effects of tyrosine phosphorylation on KRAS and SFK/YAP in the design of drug combinations that target these novel crosstalk mechanisms and overcome drug resistance.
登录
查看更多内容
影响因子：
64.8
作者：
Chang L;Azzolin L;Di Biagio D;Zanconato F;Battilana G;Lucon Xiccato R;Aragona M;Giulitti S;Panciera T;Gandin A;Sigismondo G;Krijgsveld J;Fassan M;Brusatin G;Cordenonsi M;Piccolo S
通讯作者：
Piccolo S
影响因子：
--
作者：
Dosch, Austin R;Dai, Xizi;Nagathihalli, Nagaraj S
通讯作者：
Nagathihalli, Nagaraj S
人类癌症治疗中针对 RAS 信号传导的新兴策略
影响因子：
28.5
作者：
Chen K;Zhang Y;Qian L;Wang P
通讯作者：
Wang P
影响因子：
8.8
作者：
Ahmed, Tamer A.;Adamopoulos, Christos;Poulikakos, Poulikos I.
通讯作者：
Poulikakos, Poulikos I.
影响因子：
30.8
作者：
Chan-Seng-Yue, Michelle;Kim, Jaeseung C.;Notta, Faiyaz
通讯作者：
Notta, Faiyaz