Dataset Information

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

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 I?B kinase (IKK)-related kinases Tank-binding kinase-1 (TBK1) and IKK? promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKK? 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/IKK? promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKK?, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS.

SUBMITTER: Zhu Z

PROVIDER: S-EPMC3980023 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Zhu Zehua Z Aref Amir R AR Cohoon Travis J TJ Barbie Thanh U TU Imamura Yu Y Yang Shenghong S Moody Susan E SE Shen Rhine R RR Schinzel Anna C AC Thai Tran C TC Reibel Jacob B JB Tamayo Pablo P Godfrey Jason T JT Qian Zhi Rong ZR Page Asher N AN Maciag Karolina K Chan Edmond M EM Silkworth Whitney W Labowsky Mary T MT Rozhansky Lior L Mesirov Jill P JP Gillanders William E WE Ogino Shuji S Hacohen Nir N Gaudet Suzanne S Eck Michael J MJ Engelman Jeffrey A JA Corcoran Ryan B RB Wong Kwok-Kin KK Hahn William C WC Barbie David A DA

Cancer discovery 20140120 4

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 i ...[more]

PMID: 24444711

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Project description:Intratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1-/CD11b-, Gr1-/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1-/CD11b-, Gr1-/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

Dataset Information

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

Publications

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

Similar Datasets

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