Abstract
Target-specific agents used in melanoma are not curative, and chemokines are being implicated in drug-resistance to target-specific agents. Thus, the use of conventional agents in rationale combinations may result in optimization of therapy. Because histone deacetylases participate in tumor development and progression, the combination of the pan-inhibitor SAHA and temozolomide might provide a therapeutic advantage. Here, we show synergism between the two drugs in mutant BRAF cell lines, in association with decreased phosphorylation of cell survival proteins (e.g., C-Jun-N-terminal-kinase, JNK). In the spontaneous ret transgenic mouse melanoma model, combination therapy produced a significant disease onset delay and down-regulation of Chemokine (C-C motif) ligand 2 (CCL2), JNK, and of Myeloid-derived suppressor cell recruitment. Co-incubation with a CCL2-blocking-antibody enhanced in vitro cell sensitivity to temozolomide. Conversely, recombinant CCL2 activated JNK in human tumor melanoma cells. In keeping with these results, the combination of a JNK-inhibitor with temozolomide was synergistic. By showing that down-regulation of CCL2-driven signals by SAHA and temozolomide via JNK contributes to reduce melanoma growth, we provide a rationale for the therapeutic advantage of the drug combination. This combination strategy may be effective because of interference both with tumor cell and tumor microenvironment.
Highlights
Melanoma is an aggressive disease exhibiting a metastatic behavior and intrinsic resistance to treatment, features leading to poor prognosis
The combination between temozolomide and the pan-histone deacetylases (HDAC) inhibitor SAHA displays an improved effect in human melanoma mutant and wild-type BRAF cells
A synergistic drug interaction was evident in the five studied mutant BRAF cells – including established cell lines and cell lines recently derived from patients - as supported by the combination index (CI) values (Supplementary Figure S1)
Summary
Melanoma is an aggressive disease exhibiting a metastatic behavior and intrinsic resistance to treatment, features leading to poor prognosis. In spite of the development of target-specific agents (i.e., BRAF inhibitors) which have improved progression-free survival and responsiveness to immune intervention (e.g., anti CTLA4/PD1 antibodies, Ipilumab/Yervoy), metastatic melanoma is still incurable [1,2,3]. Deregulation of survival pathways as a consequence of BRAF mutation is a frequent event [7]. Because BRAF signals through the MAPK pathway, such a pathway is recognized as relevant in melanoma cell survival. Besides being activated by BRAF mutation, the MAPK pathway hyper-activation can be achieved by deregulated expression of tyrosine kinases including those of the HER family and RET [8, 9]. Besides MAPK activation, gene-specific mutation signals triggered by mutant BRAF on other pathways have been reported to lead to transcriptional changes [10]. Altered DNA methylation or acetylation may participate to regulate such changes [11]
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