Research Papers:

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

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

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Oncotarget. 2018; 9:6174-6187. https://doi.org/10.18632/oncotarget.23485

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Renier Heijkants1, Karen Willekens2,3, Mark Schoonderwoerd4, Amina Teunisse1, Maaike Nieveen1, Enrico Radaelli5, Luuk Hawinkels4, Jean-Christophe Marine2,3 and Aart Jochemsen1

1Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

2Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, Leuven, Belgium

3Department of Oncology, KU Leuven, Leuven, Belgium

4Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, The Netherlands

5Mouse Histopathology Core Facility, VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium

Correspondence to:

Aart Jochemsen, email: [email protected]

Keywords: metastasized melanoma; CDK; HDAC; apoptosis; synergism

Received: August 25, 2017     Accepted: October 25, 2017     Published: December 15, 2017


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.

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