@article{4026824afa2b4d3dace91dfac6ba9d25,
title = "ErbB3 phosphorylation as central event in adaptive resistance to targeted therapy in metastatic melanoma: Early detection in CTCs during therapy and insights into regulation by autocrine neuregulin",
abstract = "In recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are at the basis of drug resistance. Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi. In this paper we focus on the involvement of activation of ErbB3 receptor following early exposure of melanoma cells to BRAF or MEK inhibitors, and the following induction of PI3K/AKT pathway. Although different mechanisms have been invoked in the past at the basis of this activation we show here with a combination of approaches that autocrine production of neuregulin by melanoma cells is a major factor responsible for ErbB3 phosphorylation and downstream AKT activation. Interestingly the kinetic of neuregulin production and of the ensuing ErbB3 phosphorylation is different in different melanoma cell lines which underscores the high degree of tumor heterogeneity. Moreover, heterogeneity is further highlighted by the evidence that in different cell lines neuregulin upregulation can occur at the transcriptional or at the post-transcritpional level. Finally we complement our study by showing with a liquid biopsy assay that circulating tumor cells (CTCs) from melanoma patients undergo upregulation of ErbB3 phosphorylation in vivo shortly after initiation of therapy.",
keywords = "Adaptive resistance, CTCs, ErbB3 phosphorylation, Melanoma, Neuregulin1, Target therapy",
author = "Ruggiero, {Ciro Francesco} and Debora Malpicci and Luigi Fattore and Gabriele Madonna and Vito Vanella and Domenico Mallardo and Domenico Liguoro and Valentina Salvati and Mariaelena Capone and Barbara Bedogni and Ascierto, {Paolo Antonio} and Rita Mancini and Gennaro Ciliberto",
note = "Funding Information: This work was supported by AIRC grant IG 15216 to G. Ciliberto; RM was supported by AIRC grant IG IG17009 and the Lazioinova grant 2018 n.85-2017-13750; LF was supported by AIRC/FIRC fellowship and is a recipient of a fellowship granted by Istituto Pasteur Italia- Fondazione Cenci Bolognetti; C.F.R. is a recipient of a fellowship by Intergruppo Melanoma Italiano (IMI). Funding Information: Funding: This work was supported by AIRC grant IG 15216 to G. Ciliberto; RM was supported by AIRC grant IG IG17009 and the Lazioinova grant 2018 n.85-2017-13750; LF was supported by AIRC/FIRC fellowship and is a recipient of a fellowship granted by Istituto Pasteur Italia-Fondazione Cenci Bolognetti; C.F.R. is a recipient of a fellowship by Intergruppo Melanoma Italiano (IMI). Funding Information: Conflicts of Interest: All The authors declare no conflict of interest with the exception of P.A.A. P.A.A. has advisory/consultant role for BMS, Roche-Genentech, MSD, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, Newlink Genetics, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC. P.A.A. receives research funds from BMS, Roche-Genentech, Array and travel support from MSD. The funders of this study had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Publisher Copyright: {\textcopyright} 2019 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2019",
month = oct,
doi = "10.3390/cancers11101425",
language = "English (US)",
volume = "11",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "10",
}