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

  • Cancer Discov. 2014 Apr;4(4):452-65. doi: 10.1158/2159-8290.CD-13-0646.
Zehua Zhu  1 ,  Amir R Aref ,  Travis J Cohoon ,  Thanh U Barbie ,  Yu Imamura ,  Shenghong Yang ,  Susan E Moody ,  Rhine R Shen ,  Anna C Schinzel ,  Tran C Thai ,  Jacob B Reibel ,  Pablo Tamayo ,  Jason T Godfrey ,  Zhi Rong Qian ,  Asher N Page ,  Karolina Maciag ,  Edmond M Chan ,  Whitney Silkworth ,  Mary T Labowsky ,  Lior Rozhansky ,  Jill P Mesirov ,  William E Gillanders ,  Shuji Ogino ,  Nir Hacohen ,  Suzanne Gaudet ,  Michael J Eck ,  Jeffrey A Engelman ,  Ryan B Corcoran ,  Kwok-Kin Wong ,  William C Hahn ,  David A Barbie
Affiliations
  • 1. 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.
PMID: 24444711 DOI: 10.1158/2159-8290.CD-13-0646
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.

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