Inflammation as a driver and vulnerability of KRAS mediated oncogenesis.
Inflammation as a driver and vulnerability of KRAS mediated oncogenesis.
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DOI：
10.1016/j.semcdb.2016.06.009
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发表时间：
2016-10
影响因子：
7.3
通讯作者：
Barbie DA
中科院分区：
文献类型：
--
作者：
Kitajima S;Thummalapalli R;Barbie DA
虽然通过针对某些致癌基因在癌症治疗方面取得了重要进展，但其中最常见的 KRAS 仍然难以适应这种方法。近年来，人们对炎症在促进 KRAS 驱动的肿瘤发生中的至关重要性有了更深入的认识，并且适用于肺、胰腺和结直肠肿瘤发生的不同背景。在这里，我们回顾了为什么这些组织类型特别容易发生 KRAS 突变，以及炎症如何与 KRAS 信号传导共同促进癌变。我们讨论了多种证据，证明 NF-κB、STAT3 和某些细胞因子是这些信号的关键转导因子，并且数据表明针对这些通路具有显着的临床潜力。此外，最近的工作已经开始揭示炎症信号如何与其他 KRAS 调节的生存途径（例如自噬和 MAPK 信号）相互作用，并且可能需要共同靶向这些多个节点才能获得真正的益处。此外，KRAS 相关炎症信号对更大肿瘤微环境的影响也已变得明显，通过结合利用 T 细胞抗肿瘤反应的方法来利用这种炎症代表了另一种有前途的治疗策略。最后，我们强调 KRAS 突变肿瘤的基因组复杂性最终将需要这些治疗方法的定制应用，并且在肿瘤发展过程的早期针对炎症可能对根除这种致命疾病产生最大的影响。
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.
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影响因子：
32.4
作者：
Joshi NS;Akama-Garren EH;Lu Y;Lee DY;Chang GP;Li A;DuPage M;Tammela T;Kerper NR;Farago AF;Robbins R;Crowley DM;Bronson RT;Jacks T
通讯作者：
Jacks T
影响因子：
32.4
作者：
Ebert, Peter J. R.;Cheung, Jeanne;Mellman, Ira
通讯作者：
Mellman, Ira
影响因子：
50.3
作者：
Duran, Angeles;Linares, Juan F.;Moscat, Jorge
通讯作者：
Moscat, Jorge
影响因子：
15.9
作者：
Collins, Meredith A.;Bednar, Filip;di Magliano, Marina Pasca
通讯作者：
di Magliano, Marina Pasca
炎症和大肠癌：结肠炎相关的肿瘤。
影响因子：
9
作者：
Grivennikov, Sergei I.
通讯作者：
Grivennikov, Sergei I.