|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Zhu, Z, Aref, AR, Cohoon, TJ, Barbie, TU, Imamura, Y, Yang, S, Moody, SE, Shen, RR, Schinzel, AC, Thai, TC, Reibel, JB, Tamayo, P, Godfrey, JT, Qian, ZR, Page, AN, Maciag, K, Chan, EM, Silkworth, W, Labowsky, MT, Rozhansky, L, Mesirov, JP, Gillanders, WE, Ogino, S, Hacohen, N, Gaudet, S, Eck, MJ, Engelman, JA, Corcoran, RB, Wong, KK, Hahn, WC, Barbie, DA|
Although the roles of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here we show that the IKK-related kinases TBK1 and IKKε promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and 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 and MEK inhibitor therapy 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, JAK, and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS.