title: Skin tumorigenesis stimulated by Raf inhibitors relies upon Raf functions that are dependent and independent of ERK.
abstract: RAF inhibitors achieve unprecedented but mainly transient clinical responses in patients with melanoma whose tumors harbor an activating BRAF mutation. One notable side-effect of RAF inhibitors is the stimulation of cutaneous skin tumors, arising in about 30% of patients receiving these drugs, which are thought to develop as a result of inhibitor-induced activation of wild-type Raf in occult precursor skin lesions. This effect raises the possibility that less manageable tumors might also arise in other epithelial tissues. Here we provide preclinical evidence supporting this disquieting hypothesis by showing that the RAF inhibitors PLX-4032 (vemurafenib) and GDC-0879 precipitate the development of cell-autonomous, Ras-driven tumors in skin and gastric epithelia. The magnitude of the effects correlated with the inhibitors' relative abilities to induce ERK activation. Epidermis-restricted ablation of either B-Raf or C-Raf prevented PLX-4032-induced ERK activation and tumorigenesis. In contrast, GDC-0879 induced ERK activation and tumorigenesis in B-Raf-deficient epidermis, whereas C-Raf ablation blocked GDC-0879-induced tumorigenesis (despite strong ERK activation) by preventing Rokα-mediated keratinocyte dedifferentiation. Thus, inhibitor-induced ERK activation did not require a specific Raf kinase. ERK activation was necessary, but not sufficient for Ras + Raf inhibitor-induced tumorigenesis, whereas C-Raf downregulation of Rokα was essential even in the face of sustained ERK signaling to prevent differentiation and promote tumorigenesis. Taken together, our findings suggest that combination therapies targeting ERK-dependent and -independent functions of Raf may be more efficient but also safer for cancer treatment.
authors.affiliation: Authors' Affiliation: Department of Microbiology, Immunobiology and Genetics, University of Vienna, Max F. Perutz Laboratories, Vienna, Austria.
authors.forename: Eszter
authors.initials: E
authors.lastname: Doma
authors.forename: Christian
authors.initials: C
authors.lastname: Rupp
authors.forename: Andrea
authors.initials: A
authors.lastname: Varga
authors.forename: Florian
authors.initials: F
authors.lastname: Kern
authors.forename: Bettina
authors.initials: B
authors.lastname: Riegler
authors.forename: Manuela
authors.initials: M
authors.lastname: Baccarini
mesh_terms: D000818:Animals; D019556:COS Cells; D063646:Carcinogenesis / Q000187:drug effects*; D002522:Chlorocebus aethiops; D006801:Humans; D007192:Indenes / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008545:Melanoma / Q000139:chemically induced*; D051379:Mice; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011720:Pyrazoles / Q000494:pharmacology; D012878:Skin Neoplasms / Q000139:chemically induced*; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000077484:Vemurafenib; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: C540167:2-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol; D007192:Indenes; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000077484:Vemurafenib; D048490:raf Kinases