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

Zehua Zhu1, Amir R Aref, Travis J Cohoon

  • 1Departments 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.

Cancer Discovery
|January 22, 2014
PubMed

Insights

Tank-binding kinase-1 (TBK1) and IKKε promote KRAS-driven lung cancer by regulating cytokines. Inhibiting these kinases with CYT387, alongside MEK, halts tumor growth and promotes regression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways are crucial in KRAS-driven cancers.
  • KRAS also utilizes other pathways for tumor maintenance, presenting therapeutic targets.

Purpose of the Study:

  • To investigate the role of IκB kinase (IKK)-related kinases, specifically TBK1 and IKKε, in KRAS-driven tumorigenesis.
  • To evaluate the efficacy of the JAK/TBK1/IKKε inhibitor CYT387, alone and in combination with MAPK pathway inhibitors, in preclinical models.

Main Methods:

  • Investigated the role of TBK1 and IKKε in regulating autocrine cytokine production (CCL5, IL-6) in KRAS-driven tumors.
  • Utilized CYT387, a potent inhibitor of JAK/TBK1/IKKε, in Kras-driven murine lung cancer models.
  • Assessed the impact of combined CYT387 and MEK inhibition on tumor growth and regression.

Main Results:

  • TBK1 and IKKε were found to promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and IL-6.
  • CYT387 treatment effectively inhibited RAS-associated cytokine signaling and impaired Kras-driven lung cancer growth.
  • Combined treatment with CYT387 and MEK inhibitors led to the regression of aggressive Kras-mutant, p53-null lung adenocarcinomas.

Conclusions:

  • TBK1/IKKε kinases are critical for tumor cell survival in KRAS-driven cancers via CCL5 and IL-6.
  • Concurrent inhibition of TBK1/IKKε, JAK, and MEK signaling represents a promising therapeutic strategy against oncogenic KRAS.

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