Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit
| Autor: | William C. Hahn, Shenghong Yang, Susan Moody, Nir Hacohen, David A. Barbie, Ryan B. Corcoran, Mary T. Labowsky, Whitney Silkworth, Amir Reza Aref, Jason T. Godfrey, Karolina Maciag, Tran C. Thai, Lior Rozhansky, Yu Imamura, Zehua Zhu, Pablo Tamayo, Rhine R. Shen, Thanh U. Barbie, Asher N. Page, Travis J. Cohoon, Kwok-Kin Wong, Jacob B. Reibel, Jeffrey A. Engelman, Anna C. Schinzel, Zhi Rong Qian, Shuji Ogino, Jill P. Mesirov, William E. Gillanders, Suzanne Gaudet, Michael J. Eck, Edmond M. Chan |
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| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_treatment Biology Protein Serine-Threonine Kinases medicine.disease_cause Article Mice TANK-binding kinase 1 Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Human Umbilical Vein Endothelial Cells Animals Humans Autocrine signalling neoplasms Chemokine CCL5 Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Kinase Interleukin-6 MEK inhibitor Neoplasms Experimental digestive system diseases respiratory tract diseases Autocrine Communication Cytokine Pyrimidines Oncology Benzamides Cancer research ras Proteins I-kappa B Proteins KRAS Signal Transduction |
| Zdroj: | Cancer discovery. 4(4) |
| ISSN: | 2159-8290 |
| Popis: | Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the IκB kinase (IKK)–related kinases Tank-binding kinase-1 (TBK1) and IKKϵ promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKϵ inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKKϵ promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKϵ, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS. Significance: In addition to activating MAPK and PI3K, oncogenic KRAS engages cytokine signaling to promote tumorigenesis. CYT387, originally described as a selective JAK inhibitor, is also a potent TBK/IKKϵ inhibitor that uniquely disrupts a cytokine circuit involving CCL5, IL-6, and STAT3. The efficacy of CYT387-based treatment in murine Kras-driven lung cancer models uncovers a novel therapeutic approach for these refractory tumors with immediate translational implications. Cancer Discov; 4(4); 452–65. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 377 |
| Databáze: | OpenAIRE |
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