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.
Highlights
Malignant melanoma is the most aggressive tumour of the skin, which arises from the transformation of melanocytes
In order to confirm if the main mechanism responsible for ErbB3 phosphorylation observed in melanoma cells exposed to B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitors is the activation of an autocrine loop, we assessed the effect
In order to confirm if the main mechanism responsible for ErbB3 phosphorylation observed in melanoma cells exposed to BRAF inhibitors is the activation of an autocrine loop, we assessed the of the conditioned medium medium (CM) obtained different lines after with vemurafenib effect of the conditioned (CM) from obtained fromcell different cellincubation lines after incubation with as a
Summary
Malignant melanoma is the most aggressive tumour of the skin, which arises from the transformation of melanocytes. 90% of cases, and other mutations V600K-D-R may occur [4] All these aminoacid substitutions result in constitutive kinase activation and uncontrolled cell growth. This led initially to the clinical development of BRAF inhibitors such as vemurafenib or dabrafenib with promising results in terms of high objective response rates, and improved survival [5]. The strong evidence that disease relapse due to drug resistance occurs shortly after initiation of BRAF inhibitor monotherapy, and that this is linked to the emergence of bypass mutations in resistant tumours which cause reactivation of the RAS/BRAF/MEK pathway [2], led to the development of dual therapies with BRAF and MEK inhibitors. Dual therapy, being able to provide more durable disease control and improved survival vs. monotherapy, is plagued by the development of drug resistance [2,6]
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