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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

1
Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
2
Department of Experimental and Clinical Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
3
Department of Molecular and Clinical Medicine, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, University of Rome “Sapienza”, 00161 Rome, Italy
4
Department of Melanoma, Oncologic Immunotherapy and Innovative Therapies Istituto Nazionale Tumori IRCCS, “Fondazione G. Pascale”, 80131 Naples, Italy
5
Department of Molecular and Clinical Medicine, University of Rome “Sapienza”, 00161 Rome, Italy
6
Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA
7
Department of Dermatology, Miller School of Medicine, Miami, FL 33136, USA
8
Scientific Directorate, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
*
Author to whom correspondence should be addressed.
These two authors contributed equally.
These two authors contributed equally.
Cancers 2019, 11(10), 1425; https://doi.org/10.3390/cancers11101425
Received: 8 August 2019 / Revised: 20 September 2019 / Accepted: 20 September 2019 / Published: 25 September 2019
(This article belongs to the Special Issue Targeted Therapies for Melanoma)
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. View Full-Text
Keywords: melanoma; target therapy; adaptive resistance; ErbB3 phosphorylation; CTCs; neuregulin1 melanoma; target therapy; adaptive resistance; ErbB3 phosphorylation; CTCs; neuregulin1
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MDPI and ACS Style

Ruggiero, C.F.; Malpicci, D.; Fattore, L.; Madonna, G.; Vanella, V.; Mallardo, D.; Liguoro, D.; Salvati, V.; Capone, M.; Bedogni, B.; Ascierto, P.A.; Mancini, R.; Ciliberto, G. 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. Cancers 2019, 11, 1425. https://doi.org/10.3390/cancers11101425

AMA Style

Ruggiero CF, Malpicci D, Fattore L, Madonna G, Vanella V, Mallardo D, Liguoro D, Salvati V, Capone M, Bedogni B, Ascierto PA, Mancini R, Ciliberto G. 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. Cancers. 2019; 11(10):1425. https://doi.org/10.3390/cancers11101425

Chicago/Turabian Style

Ruggiero, Ciro F.; Malpicci, Debora; Fattore, Luigi; Madonna, Gabriele; Vanella, Vito; Mallardo, Domenico; Liguoro, Domenico; Salvati, Valentina; Capone, Mariaelena; Bedogni, Barbara; Ascierto, Paolo A.; Mancini, Rita; Ciliberto, Gennaro. 2019. "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" Cancers 11, no. 10: 1425. https://doi.org/10.3390/cancers11101425

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