Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit.
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.
Departments of 1Medical Oncology and 2Cancer Biology, Dana-Farber Cancer Institute; 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston; 4Broad Institute of Harvard and MIT, Cambridge; 5MGH Cancer Center, 6Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts; and 7Department of Surgery, Division of Biology and Biomedical Sciences, Washington University, St. Louis, Missouri.
Zehua
Z
Zhu
Amir R
AR
Aref
Travis J
TJ
Cohoon
Thanh U
TU
Barbie
Yu
Y
Imamura
Shenghong
S
Yang
Susan E
SE
Moody
Rhine R
RR
Shen
Anna C
AC
Schinzel
Tran C
TC
Thai
Jacob B
JB
Reibel
Pablo
P
Tamayo
Jason T
JT
Godfrey
Zhi Rong
ZR
Qian
Asher N
AN
Page
Karolina
K
Maciag
Edmond M
EM
Chan
Whitney
W
Silkworth
Mary T
MT
Labowsky
Lior
L
Rozhansky
Jill P
JP
Mesirov
William E
WE
Gillanders
Shuji
S
Ogino
Nir
N
Hacohen
Suzanne
S
Gaudet
Michael J
MJ
Eck
Jeffrey A
JA
Engelman
Ryan B
RB
Corcoran
Kwok-Kin
KK
Wong
William C
WC
Hahn
David A
DA
Barbie
D000818:Animals; D019898:Autocrine Communication; D001549:Benzamides / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D018631:ras Proteins / Q000235:genetics*
D001549:Benzamides; D018946:Chemokine CCL5; D020672:I-kappa B Proteins; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; D017346:Protein Serine-Threonine Kinases; D018631:ras Proteins