Abstract 4603: Targeted treatment of metastatic melanoma through interference with Pin1-FOXM1 signaling
Authors: Kruiswijk Flore , Hasenfuss Sebastian E. , Sivapatham Renuka , Broek Niels J.F. van den , Kruit Wim , Brenkman Arjan B. , Campisi Judith , Burgering Boudewijn M.T. , Hoeijmakers Jan H.J. , Keizer Peter L.J. de 
Published: May 2015

Abstract
Malignant melanoma is the most lethal form of skin cancer. Inhibition of BRAF/MEK signaling or activation of T-cell signaling are the current options for therapeutic intervention. These therapies however only provide a short term clinical benefit and development of complementary strategies is still needed. We set out to identify new molecular targets to improve therapeutic intervention in melanoma.
Database meta-analysis revealed the pro-proliferative and pro-survival protein FOXM1 to be strongly elevated in malignant melanoma and progressively expressed with advances disease state. A follow-up search for potential enzymes that may regulate FOXM1 activity identified the peptidyl-prolyl isomerase Pin1 to be closely associated with FOXM1 expression and FOXM1 activity. Pin1 and active FOXM1 signaling proved to be indicative for poor disease outcome and as such we set out to address whether modulation of Pin1-FOXM1 signaling could be beneficial against melanoma.
Here, we show that Pin1-FOXM1 signaling is a targetable point of intervention in melanoma. We observed that Pin1 is essential for FOXM1 activity through physical interaction in the G2/M phase of the cell cycle. The Pin1-FOXM1 interaction is dependent on MEK-mediated phosphorylation of FOXM1 and mutation of the MEK phosphorylated residues in FOXM1 abrogated the interaction with Pin1. The Pin1-FOXM1 interaction is enhanced by BRAFV600E, the driver oncogene in the majority of melanomas, which prompted us to investigate the consequence of Pin1 inhibition on FOXM1 activity and tumor progression in BRAFV600E-driven melanoma. Excitingly, in that background we observed that interference with Pin1 strongly inhibited FOXM1 activity and tumor outgrowth.
In order to repress Pin1-FOXM1 signaling in a clinically applicable manner, we designed a targeted therapy. Importantly, interference with Pin1-FOXM1 signaling in this manner markedly repressed growth of melanoma cells and human metastatic melanoma ex vivo. Thus, we observed here that elevated Pin1-FOXM1 signaling is indicative of poor prognosis in melanoma and therapeutic inhibition of Pin1-FOXM1 signaling shows promising results as melanoma treatment opening new perspectives for clinical intervention.
This work is supported by post-doctoral fellowship Buit-4649 of the Dutch Cancer Society awarded to PLJDK
Citation Format: Flore Kruiswijk, Sebastian E. Hasenfuss, Renuka Sivapatham, Niels J.F. van den Broek, Wim Kruit, Arjan B. Brenkman, Judith Campisi, Boudewijn M.T. Burgering, Jan H.J. Hoeijmakers, Peter L.J. de Keizer. Targeted treatment of metastatic melanoma through interference with Pin1-FOXM1 signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4603. doi:10.1158/1538-7445.AM2014-4603