Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors
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Kotryna Seip1, Karianne G. Fleten1,*, Anna Barkovskaya1,*, Vigdis Nygaard1, Mads H. Haugen1, Birgit Ø. Engesæter1, Gunhild M. Mælandsmo1,2,3, Lina Prasmickaite1
1Department of Tumor Biology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
2K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
3Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
*These authors have contributed equally to this work
Lina Prasmickaite, email: [email protected]
Keywords: melanoma, BRAF inhibitor, resistance, phenotype switch, fibroblasts
Received: October 30, 2015 Accepted: February 16, 2016 Published: February 24, 2016
The knowledge on how tumor-associated stroma influences efficacy of anti-cancer therapy just started to emerge. Here we show that lung fibroblasts reduce melanoma sensitivity to the BRAF inhibitor (BRAFi) vemurafenib only if the two cell types are in close proximity. In the presence of fibroblasts, the adjacent melanoma cells acquire de-differentiated mesenchymal-like phenotype. Upon treatment with BRAFi, such melanoma cells maintain high levels of phospho ribosomal protein S6 (pS6), i.e. active mTOR signaling, which is suppressed in the BRAFi sensitive cells without stromal contacts. Inhibitors of PI3K/mTOR in combination with BRAFi eradicate pS6high cell subpopulations and potentiate anti-cancer effects in melanoma protected by the fibroblasts. mTOR and BRAF co-inhibition also delayed the development of early-stage lung metastases in vivo. In conclusion, we demonstrate that upon influence from fibroblasts, melanoma cells undergo a phenotype switch to the mesenchymal state, which can support PI3K/mTOR signaling. The lost sensitivity to BRAFi in such cells can be overcome by co-targeting PI3K/mTOR. This knowledge could be explored for designing BRAFi combination therapies aiming to eliminate both stroma-protected and non-protected counterparts of metastases.
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