| First Author | Zhu Z | Year | 2014 |
| Journal | Cancer Discov | Volume | 4 |
| Issue | 4 | Pages | 452-65 |
| PubMed ID | 24444711 | Mgi Jnum | J:212507 |
| Mgi Id | MGI:5581585 | Doi | 10.1158/2159-8290.CD-13-0646 |
| Citation | Zhu Z, et al. (2014) Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov 4(4):452-65 |
| abstractText | 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 IkappaB kinase (IKK)-related kinases Tank-binding kinase-1 (TBK1) and IKKepsilon promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKepsilon 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/IKKepsilon promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKepsilon, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS. |
