Targeting cytokine networks in KRAS-driven tumorigenesis

Golay, Hadrien; Barbie, David A.

doi:10.1586/14737140.2014.928596

Cited by 16 publications

(19 citation statements)

References 20 publications

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“…In agreement with this data, low mRNA expression levels of lL6 , Tnfα and IL8 (the human orthologue to murine Cxcl1 ) were also associated with a better prognosis in lung AC patients harboring K‐RAS mutations . Thus, these data indicate that lL6 , Tnfα and Cxcl1 play a central role for K‐RAS driven lung AC both in human and mice and provides a solid rationality for using agents blocking inflammation‐driven tumorigenesis, such as ruxolitinib, to treat lung AC …”

Section: Discussionmentioning

confidence: 80%

“…While EGFR tyrosine kinase inhibitors, such as erlotinib, gefitinib or afatinib, are part of the clinical routine to treat EGFR ‐mutated lung AC patients, the development of K‐RAS inhibitors has been less successful so far, with no K‐RAS‐based targeted therapy being clinically approved . Hence, targeting alternative tumor drivers fueling K‐RAS‐mediated lung tumorigenesis such as tumor‐promoting inflammation and K‐RAS downstream effector pathways are considered to be a promising treatment strategy …”

Section: Introductionmentioning

confidence: 99%

“…JAK signaling either promotes or suppresses tumorigenesis in a tumor cell intrinsic manner. Indeed, K‐RAS ‐mutated lung AC cells secrete pro‐inflammatory cytokines including interleukin (IL)‐6 that activate JAK1 and JAK2 via glycoprotein 130 in an autocrine loop, thereby promoting tumor cell survival . On the other hand, genetic deletion of STAT3, a key signaling mediator of JAK1/2, enhances K‐RAS‐driven lung tumorigenesis, and activation of the interferon/JAK/STAT axis induces cell apoptosis and suppresses tumorigenesis in various experimental tumor models …”

Section: Introductionmentioning

confidence: 99%

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JAK–STAT inhibition impairs K‐RAS‐driven lung adenocarcinoma progression

Mohrherr

Haber

Breitenecker

et al. 2019

Intl Journal of Cancer

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Oncogenic K‐RAS has been difficult to target and currently there is no K‐RAS‐based targeted therapy available for patients suffering from K‐RAS‐driven lung adenocarcinoma (AC). Alternatively, targeting K‐RAS‐downstream effectors, K‐RAS‐cooperating signaling pathways or cancer hallmarks, such as tumor‐promoting inflammation, has been shown to be a promising therapeutic strategy. Since the JAK–STAT pathway is considered to be a central player in inflammation‐mediated tumorigenesis, we investigated here the implication of JAK–STAT signaling and the therapeutic potential of JAK1/2 inhibition in K‐RAS‐driven lung AC. Our data showed that JAK1 and JAK2 are activated in human lung AC and that increased activation of JAK–STAT signaling correlated with disease progression and K‐RAS activity in human lung AC. Accordingly, administration of the JAK1/2 selective tyrosine kinase inhibitor ruxolitinib reduced proliferation of tumor cells and effectively reduced tumor progression in immunodeficient and immunocompetent mouse models of K‐RAS‐driven lung AC. Notably, JAK1/2 inhibition led to the establishment of an antitumorigenic tumor microenvironment, characterized by decreased levels of tumor‐promoting chemokines and cytokines and reduced numbers of infiltrating myeloid derived suppressor cells, thereby impairing tumor growth. Taken together, we identified JAK1/2 inhibition as promising therapy for K‐RAS‐driven lung AC.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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JAK–STAT inhibition impairs K‐RAS‐driven lung adenocarcinoma progression

Mohrherr

Haber

Breitenecker

et al. 2019

Intl Journal of Cancer

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“…David Barbie and co-workers [52–54] describe the involvement of inflammation (as well as its major components: NF-κB, STAT3 and secreted cytokines, such as IL6) in the activation of KRAS signaling inducing a variety of survival pathways, such as MAPK signaling and autophagy. The authors have highlighted the importance of targeting inflammation early in the course of tumor development (such as the effect of COX2 inhibition by aspirin or other non-steroidal anti-inflammatory agents hindering colorectal cancer development [55]).…”

Section: The Role Of Inter-cellular Signaling In Cancer Initiationmentioning

confidence: 99%

Intracellular and intercellular signaling networks in cancer initiation, development and precision anti-cancer therapy

Csermely

Korcsmáros

Nussinov

2016

Seminars in Cell & Developmental Biology

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Cancer initiation and development are increasingly perceived as systems-level phenomena, where intra- and inter-cellular signaling networks of the ecosystem of cancer and stromal cells offer efficient methodologies for outcome prediction and intervention design. Within this framework, RAS emerges as a ‘contextual signaling hub’, i.e. the final result of RAS activation or inhibition is determined by the signaling network context. Current therapies often ‘train’ cancer cells shifting them to a novel attractor, which has increased metastatic potential and drug resistance. The few therapy-surviving cancer cells are surrounded by massive cell death triggering a primordial adaptive and reparative general wound healing response. Overall, dynamic analysis of patient- and disease-stage specific intracellular and intercellular signaling networks may open new areas of anticancer therapy using multitarget drugs, drugs combinations, edgetic drugs, as well as help design ‘gentler’, differentiation and maintenance therapies.

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“…Activating mutations in KRAS endow epithelial cells with the capacity to survive and expand in this setting, often fueled by the same cytokines that are attempting to recruit inflammatory cells and fend them off [2]. Indeed, the most common tumors in which KRAS mutations are observed arise from the epithelial linings of organs – lung, pancreas, and colon - that sustain both mutational and inflammatory insults over the course of time (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Inflammation as a driver and vulnerability of KRAS mediated oncogenesis

Kitajima

Thummalapalli

Barbie

2016

Seminars in Cell & Developmental Biology

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While important strides have been made in cancer therapy by targeting certain oncogenes, KRAS, the most common among them, remains refractory to this approach. In recent years, a deeper understanding of the critical importance of inflammation in promoting KRAS-driven oncogenesis has emerged, and applies across the different contexts of lung, pancreatic, and colorectal tumorigenesis. Here we review why these tissue types are particularly prone to developing KRAS mutations, and how inflammation conspires with KRAS signaling to fuel carcinogenesis. We discuss multiple lines of evidence that have established NF-κB, STAT3, and certain cytokines as key transducers of these signals, and data to suggest that targeting these pathways has significant clinical potential. Furthermore, recent work has begun to uncover how inflammatory signaling interacts with other KRAS regulated survival pathways such as autophagy and MAPK signaling, and that co-targeting these multiple nodes may be required to achieve real benefit. In addition, the impact of KRAS associated inflammatory signaling on the greater tumor microenvironment has also become apparent, and taking advantage of this inflammation by incorporating approaches that harness T cell anti-tumor responses represents another promising therapeutic strategy. Finally, we highlight the likelihood that the genomic complexity of KRAS mutant tumors will ultimately require tailored application of these therapeutic approaches, and that targeting inflammation early in the course of tumor development could have the greatest impact on eradicating this deadly disease.

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Targeting cytokine networks in KRAS-driven tumorigenesis

Cited by 16 publications

References 20 publications

JAK–STAT inhibition impairs K‐RAS‐driven lung adenocarcinoma progression

JAK–STAT inhibition impairs K‐RAS‐driven lung adenocarcinoma progression

Intracellular and intercellular signaling networks in cancer initiation, development and precision anti-cancer therapy

Inflammation as a driver and vulnerability of KRAS mediated oncogenesis

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