Inflammation as a driver and vulnerability of KRAS mediated oncogenesis

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• 作者：Shunsuke Kitajima^a ; ^{shunsuke_kitajima@dfci.harvard.edu" class="auth_mail" title="E-mail the corresponding author} ; Rohit Thummalapalli^a ; ^b ; ^{rohit_thummalapalli@hms.harvard.edu" class="auth_mail" title="E-mail the corresponding author} ; David A. Barbie^a ; ^{dbarbie@partners.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：KRAS ; Inflammation ; NF-κB ; STAT3 ; Cytokines ; Autophagy
• 刊名：Seminars in Cell & Developmental Biology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：58
• 期：Complete
• 页码：127-135
• 全文大小：1591 K

文摘

While important strides have been made in cancer therapy by targeting certain oncogenes, KRAS, the most common among them, remains refractory to this approach. In recent years, a deeper understanding of the critical importance of inflammation in promoting KRAS-driven oncogenesis has emerged, and applies across the different contexts of lung, pancreatic, and colorectal tumorigenesis. Here we review why these tissue types are particularly prone to developing KRAS mutations, and how inflammation conspires with KRAS signaling to fuel carcinogenesis. We discuss multiple lines of evidence that have established NF-κB, STAT3, and certain cytokines as key transducers of these signals, and data to suggest that targeting these pathways has significant clinical potential. Furthermore, recent work has begun to uncover how inflammatory signaling interacts with other KRAS regulated survival pathways such as autophagy and MAPK signaling, and that co-targeting these multiple nodes may be required to achieve real benefit. In addition, the impact of KRAS associated inflammatory signaling on the greater tumor microenvironment has also become apparent, and taking advantage of this inflammation by incorporating approaches that harness T cell anti-tumor responses represents another promising therapeutic strategy. Finally, we highlight the likelihood that the genomic complexity of KRAS mutant tumors will ultimately require tailored application of these therapeutic approaches, and that targeting inflammation early in the course of tumor development could have the greatest impact on eradicating this deadly disease.