Combined inhibition of CDK and HDAC as a promising therapeutic strategy for both cutaneous and uveal metastatic melanoma.

Renier Heijkants,Amina Teunisse,Luuk Hawinkels,Maaike Nieveen,Enrico Radaelli,Jean-Christophe Marine,Mark Schoonderwoerd,Karen Willekens,Aart Jochemsen

doi:10.18632/oncotarget.23485

Renier Heijkants, Amina Teunisse + Show 7 more

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https://doi.org/10.18632/oncotarget.23485

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Abstract

Very little to no improvement in overall survival has been seen in patients with advanced non-resectable cutaneous melanoma or metastatic uveal melanoma in decades, highlighting the need for novel therapeutic options. In this study we investigated as a potential novel therapeutic intervention for both cutaneous and uveal melanoma patients a combination of the broad spectrum HDAC inhibitor quisinostat and pan-CDK inhibitor flavopiridol. Both drugs are currently in clinical trials reducing time from bench to bedside. Combining quisinostat and flavopiridol shows a synergistic reduction in cell viability of all melanoma cell lines tested, irrespective of their driver mutations. This synergism was also observed in BRAFV600E mutant melanoma that had acquired resistance to BRAF inhibition. Mechanistically, loss of cell viability was, at least partly, due to induction of apoptotic cell death. The combination was also effectively inducing tumor regression in a preclinical setting, namely a patient-derived tumor xenograft (PDX) model of cutaneous melanoma, without increasing adverse effects. We propose that the quisinostat/flavopiridol combination is a promising therapeutic option for both cutaneous and uveal metastatic melanoma patients, independent of their mutational status or (acquired) resistance to BRAF inhibition.

Highlights

Melanoma is an aggressive type of cancer which originates from melanocytes, affecting about 132,000 new patients in 2016 in the US alone [1]
In this study we investigated as a potential novel therapeutic intervention for both cutaneous and uveal melanoma patients a combination of the broad spectrum histone deacetylase (HDAC) inhibitor quisinostat and pan-cyclindependent kinase (CDK) inhibitor flavopiridol
Synergistic reduction of uveal melanoma (UM) cell proliferation by simultaneous CDK and HDAC inhibition We first evaluated whether quisinostat and flavopiridol were capable of eliciting their expected biochemical responses in UM cells (Figure 1A)

Summary

Introduction

Melanoma is an aggressive type of cancer which originates from melanocytes, affecting about 132,000 new patients in 2016 in the US alone [1]. It has been shown that the continuous activation GNA11 or GNAQ exerts its oncogenic capacity, among others, through the activation of the MAPK pathway via protein kinase C (PKC) signaling [8,9,10]. This insight has incited the use of PKC inhibitors as treatment for UM, but these inhibitors only have limited clinical effects [11]. Despite these ongoing developments there still is a lack of curative treatment for metastasized UM and CM, rendering metastasized melanoma a lethal disease. Our effort to search for novel therapeutic www.impactjournals.com/oncotarget interventions for metastatic melanoma focuses on drugs in clinical development to reduce the time from bench to bedside

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