Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling.
Melanoma is the most lethal form of skin cancer and successful treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence of resistance, whereas immunotherapy is mainly effective in selected subsets of patients. Thus, there is a need to identify new targets to improve treatment of metastatic melanoma. To this extent, we searched for markers that are elevated in melanoma and are under regulation of potentially druggable enzymes. Here, we show that the pro-proliferative transcription factor FOXM1 is elevated and activated in malignant melanoma. FOXM1 activity correlated with expression of the enzyme Pin1, which we found to be indicative of a poor prognosis. In functional experiments, Pin1 proved to be a main regulator of FOXM1 activity through MEK-dependent physical regulation during the cell cycle. The Pin1-FOXM1 interaction was enhanced by BRAF(V600E), the driver oncogene in the majority of melanomas, and in extrapolation of the correlation data, interference with\ Pin1 in BRAF(V600E)-driven metastatic melanoma cells impaired both FOXM1 activity and cell survival. Importantly, cell-permeable Pin1-FOXM1-blocking peptides repressed the proliferation of melanoma cells in freshly isolated human metastatic melanoma ex vivo and in three-dimensional-cultured patient-derived melanoids. When combined with the BRAF(V600E)-inhibitor PLX4032 a robust repression in melanoid viability was obtained, establishing preclinical value of patient-derived melanoids for prognostic use of drug sensitivity and further underscoring the beneficial effect of Pin1-FOXM1 inhibitory peptides as anti-melanoma drugs. These proof-of-concept results provide a starting point for development of therapeutic Pin1-FOXM1 inhibitors to target metastatic melanoma.
Center of Molecular Medicine, Molecular Cancer Research, University Medical Center, Utrecht, The Netherlands.
F
F
Kruiswijk
Center of Molecular Medicine, Molecular Cancer Research, University Medical Center, Utrecht, The Netherlands.
S C
SC
Hasenfuss
The Buck Institute for Research on Aging, Novato, CA, USA.
R
R
Sivapatham
Department of Genetics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
M P
MP
Baar
Department of Genetics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
D
D
Putavet
Department of Genetics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
K A T
KA
Naipal
Center of Molecular Medicine, Molecular Cancer Research, University Medical Center, Utrecht, The Netherlands.
N J F
NJ
van den Broek
Department of Medical Oncology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
W
W
Kruit
Department of Bioinformatics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
P J
PJ
van der Spek
Department of Genetics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
D C
DC
van Gent
Center of Molecular Medicine, Molecular Cancer Research, University Medical Center, Utrecht, The Netherlands.|Department of Metabolic and Endocrine Diseases, University Medical Center, Utrecht, The Netherlands.
A B
AB
Brenkman
The Buck Institute for Research on Aging, Novato, CA, USA.|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
J
J
Campisi
Center of Molecular Medicine, Molecular Cancer Research, University Medical Center, Utrecht, The Netherlands.
B M T
BM
Burgering
Department of Genetics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
J H J
JH
Hoeijmakers
Center of Molecular Medicine, Molecular Cancer Research, University Medical Center, Utrecht, The Netherlands.|The Buck Institute for Research on Aging, Novato, CA, USA.|Department of Genetics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
P L J
PL
de Keizer
D045744:Cell Line, Tumor; D000072278:Forkhead Box Protein M1 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000235:genetics*; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction; D013449:Sulfonamides / Q000008:administration & dosage; D000077484:Vemurafenib
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D007211:Indoles; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C000606846:PIN1 protein, human