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Cancer discovery DOI:10.1158/2159-8290.CD-13-0646

Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit.

Publication TypeJournal Article
Year of Publication2014
AuthorsZhu, 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
JournalCancer discovery
Date Published2014/01/20

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.