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Cancer Discov 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, ZRong, 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, K-K, Hahn, WC, Barbie, DA
JournalCancer Discov
Volume4
Issue4
Pages452-65
Date Published2014 Apr
ISSN2159-8290
KeywordsAnimals, Autocrine Communication, Benzamides, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Chemokine CCL5, Human Umbilical Vein Endothelial Cells, Humans, I-kappa B Proteins, Interleukin-6, Mice, Neoplasms, Experimental, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Pyrimidines, ras Proteins, Signal Transduction
Abstract

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.

URLhttp://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24444711
DOI10.1158/2159-8290.CD-13-0646
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24444711?dopt=Abstract

Alternate JournalCancer Discov
PubMed ID24444711
PubMed Central IDPMC3980023
Grant ListU01CA141576 / CA / NCI NIH HHS / United States
R01 CA122794 / CA / NCI NIH HHS / United States
K08 CA138918 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 CA130988 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
R01 CA163896 / CA / NCI NIH HHS / United States
R01 CA166480 / CA / NCI NIH HHS / United States
R01 CA140594 / CA / NCI NIH HHS / United States
R01 CA109467 / CA / NCI NIH HHS / United States
K08 CA138918-01A1 / CA / NCI NIH HHS / United States
R01 CA154480 / CA / NCI NIH HHS / United States
R01 CA121941 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
K08 CA166510 / CA / NCI NIH HHS / United States
U01 CA141576 / CA / NCI NIH HHS / United States
R01CA140594 / CA / NCI NIH HHS / United States