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 language | English (US) |
|---|---|
| Article number | 1425 |
| Journal | Cancers |
| Volume | 11 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2019 |
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Keywords
- Adaptive resistance
- CTCs
- ErbB3 phosphorylation
- Melanoma
- Neuregulin1
- Target therapy
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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. / Ruggiero, Ciro Francesco; Malpicci, Debora; Fattore, Luigi; Madonna, Gabriele; Vanella, Vito; Mallardo, Domenico; Liguoro, Domenico; Salvati, Valentina; Capone, Mariaelena; Bedogni, Barbara; Ascierto, Paolo Antonio; Mancini, Rita; Ciliberto, Gennaro.
In: Cancers, Vol. 11, No. 10, 1425, 10.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - ErbB3 phosphorylation as central event in adaptive resistance to targeted therapy in metastatic melanoma
T2 - Early detection in CTCs during therapy and insights into regulation by autocrine neuregulin
AU - Ruggiero, Ciro Francesco
AU - Malpicci, Debora
AU - Fattore, Luigi
AU - Madonna, Gabriele
AU - Vanella, Vito
AU - Mallardo, Domenico
AU - Liguoro, Domenico
AU - Salvati, Valentina
AU - Capone, Mariaelena
AU - Bedogni, Barbara
AU - Ascierto, Paolo Antonio
AU - Mancini, Rita
AU - Ciliberto, Gennaro
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
KW - Adaptive resistance
KW - CTCs
KW - ErbB3 phosphorylation
KW - Melanoma
KW - Neuregulin1
KW - Target therapy
UR - http://www.scopus.com/inward/record.url?scp=85073435278&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073435278&partnerID=8YFLogxK
U2 - 10.3390/cancers11101425
DO - 10.3390/cancers11101425
M3 - Article
AN - SCOPUS:85073435278
VL - 11
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 10
M1 - 1425
ER -