Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK

Doma, Eszter; Rupp, Christian; Varga, Andrea; Kern, Florian; Riegler, Bettina; Baccarini, Manuela

doi:10.1158/0008-5472.can-13-0748

Cited by 20 publications

(34 citation statements)

References 29 publications

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“…The latter model confirmed that Ras activation, in the absence of other mutations or of inflammation, is enough to trigger Raf inhibitor‐driven tumorigenesis in both skin and gastric epithelia [92]. Thus, Ras + inhibitor‐induced Erk activation accelerates the growth of tumors originating from cells containing activated Ras [92,109,110]. Further common to both models is the concept that paradoxical activation of the pathway can only happen at low inhibitor concentration [92,107,108,110].…”

Section: Raf and Mek Inhibitors – Success Stories With Pitfallsmentioning

confidence: 58%

“RAF” neighborhood: Protein–protein interaction in the Raf/Mek/Erk pathway

2014

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The Raf/Mek/Erk signaling pathway, activated downstream of Ras primarily to promote proliferation, represents the best studied of the evolutionary conserved MAPK cascades. The investigation of the pathway has continued unabated since its discovery roughly 30 years ago. In the last decade, however, the identification of unexpected in vivo functions of pathway components, as well as the discovery of Raf mutations in human cancer, the ensuing quest for inhibitors, and the efforts to understand their mechanism of action, have boosted interest tremendously. From this large body of work, protein–protein interaction has emerged as a recurrent, crucial theme. This review focuses on the role of protein complexes in the regulation of the Raf/Mek/Erk pathway and in its cross-talk with other signaling cascades. Mapping these interactions and finding a way of exploiting them for therapeutic purposes is one of the challenges of future molecule-targeted therapy.

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Section: Raf and Mek Inhibitors – Success Stories With Pitfallsmentioning

confidence: 58%

“RAF” neighborhood: Protein–protein interaction in the Raf/Mek/Erk pathway

2014

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“…While each group proposed a distinct mechanism to explain the effect, several themes overlapped (Figure 2B). RAF inhibitors promoted co-immunoprecipitation of RAF isoforms as well as association with RAS-GTP at cell membranes 25,76,78 , suggesting that the inhibitors promote CRAF homo- and heterodimerization and RAS-mediated activation. Moreover, site-directed mutagenesis of the putative dimer interface rendered CRAF resistant to paradoxical activation 77 .…”

Section: Development Of Atp Competitive Inhibitors Of Raf Kinase Actimentioning

confidence: 97%

“…Indeed, studies using the K5-SOS-F transgenic mouse model, in which mice are predisposed to epidermal tumors through keratinocyte-specific expression of a dominant active, farnesylated Son of Sevenless (SOS-F), have shown that RAF inhibitor treatment promotes RAF dimerization, activates ERK signaling, and suppresses Rho-Associated, Coiled-Coil Containing Protein Kinase 2 (Rokα) to potentiate Ras -driven epidermal tumorigenesis. 78 In addition to RAS mutations, oncoviruses have been implicated as initiating factors in a subset of cutaneous lesions. Papilloma virus and Merkel cell polyomavirus DNA were identified in BRAF inhibitor treated patient samples and vemurafenib promoted tumorigenesis in an HPV driven mouse model of SCC 91 .…”

Section: Clinical Use Of Raf Inhibitorsmentioning

confidence: 99%

Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond

et al. 2014

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The identification of mutationally activated BRAF in many cancers altered our conception of the role played by the RAF family of protein kinases in oncogenesis. In this review we describe the development of BRAF inhibitors and the results that have emerged from their analysis in both the laboratory and the clinic. We discuss the spectrum of RAF mutations in human cancer and the complex interplay between tissue of origin and response to RAF inhibition. Finally, we enumerate mechanisms of resistance to BRAF inhibition that have been characterized and postulate how strategies of RAF pathway inhibition may be extended in scope to benefit, not only the thousands of patients diagnosed annually with BRAF-mutated metastatic melanoma, but also the larger patient population with malignancies harboring mutationally activated RAF genes that is ineffectively treated with the current generation of BRAF kinase inhibitors.

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“…Our results are in good agreement with data from the Rosen laboratory indicating that increased levels of wild-type Ras–GTP complexes can cooperate with Braf hypoactive mutants to trigger tumour development in epithelial cells 24 . Similarly, increasing the pool of Ras–GTP by a dominant active Sos is sufficient to induce MAPK hyperactivation and the formation of epithelial tumours in response to Raf inhibition 25 . Likewise, MAPK activation in primary keratinocytes carrying the Braf LSLD631A allele depended both on Craf and RTK signalling.…”

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confidence: 99%

A Braf kinase-inactive mutant induces lung adenocarcinoma

Nieto

Ambrogio

Esteban-Burgos

et al. 2017

Nature

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The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types1. Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis. Moreover, inactivating BRAF mutations have also been identified in a subset of KRAS-driven human lung tumours. Co-expression of Kras(G12V) and Braf(D631A) in mouse lung cells markedly enhances tumour initiation, a phenomenon mediated by Craf kinase activity2,3, and effectively accelerates tumour progression when activated in advanced lung adenocarcinomas. We also report a key role for the wild-type Braf kinase in sustaining Kras(G12V)/Braf(D631A)-driven tumours. Ablation of the wild-type Braf allele prevents the development of lung adenocarcinoma by inducing a further increase in MAPK signalling that results in oncogenic toxicity; this effect can be abolished by pharmacological inhibition of Mek to restore tumour growth. However, the loss of wild-type Braf also induces transdifferentiation of club cells, which leads to the rapid development of lethal intrabronchiolar lesions. These observations indicate that the signal intensity of the MAPK pathway is a critical determinant not only in tumour development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype.

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Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK

Cited by 20 publications

References 29 publications

“RAF” neighborhood: Protein–protein interaction in the Raf/Mek/Erk pathway

“RAF” neighborhood: Protein–protein interaction in the Raf/Mek/Erk pathway

Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond

A Braf kinase-inactive mutant induces lung adenocarcinoma

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