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

Ciro Francesco Ruggiero, Debora Malpicci, Luigi Fattore, Gabriele Madonna, Vito Vanella, Domenico Mallardo, Domenico Liguoro, Valentina Salvati, Mariaelena Capone, Barbara Bedogni, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Article number1425
JournalCancers
Volume11
Issue number10
DOIs
StatePublished - Oct 2019

Keywords

  • Adaptive resistance
  • CTCs
  • ErbB3 phosphorylation
  • Melanoma
  • Neuregulin1
  • Target therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    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. (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(10), [1425]. https://doi.org/10.3390/cancers11101425