Targeting PIM kinase enhances the activity of sunitinib in renal cell carcinoma.
BACKGROUND
Upregulation of PIM kinase expression has been reported in many malignancies, suggesting that inhibition of PIM kinase activity may be an attractive therapeutic strategy. We hypothesised that inhibition of PIM kinase activity with SGI-1776, a novel small molecule inhibitor of PIM kinase activity, would reduce the viability of renal cell carcinoma (RCC) cells and enhance the activity of sunitinib.


METHODS
Immunoblotting, qRT-PCR, and gene expression arrays were carried out to identify genes modulated by SGI-1776 treatment. The anticancer activity of SGI-1776 and sunitinib was determined by viability and apoptosis assays and in tumour xenografts in vivo.


RESULTS
Treatment with SGI-1776 led to a decrease in phosphorylated and total c-Myc levels, which resulted in the modulation of c-Myc target genes. SGI-1776 in combination with sunitinib induced a further reduction in c-Myc levels, which was associated with enhanced anticancer activity. siRNA-mediated knockdown of c-Myc demonstrated that its expression has a key role in regulating the sensitivity to the combination of SGI-1776 and sunitinib. Importantly, the combination significantly reduced tumour burden in two RCC xenograft models compared with single-agent therapy and was very well tolerated.


CONCLUSIONS
These data indicate that targeting PIM kinase signalling is a promising treatment strategy for RCC.
Department of Medicine, Institute for Drug Development, Cancer Therapy and Research Center, The University of Texas Health Science Center, 7979 Wurzbach Road, San Antonio, TX 78245, USA.
D
D
Mahalingam
C M
CM
Espitia
E C
EC
Medina
J A
JA
Esquivel
K R
KR
Kelly
D
D
Bearss
G
G
Choy
P
P
Taverna
J S
JS
Carew
F J
FJ
Giles
S T
ST
Nawrocki
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D000077210:Sunitinib
D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011724:Pyridazines; D011758:Pyrroles; C545188:SGI 1776; D051573:Proto-Oncogene Proteins c-pim-1; D000077210:Sunitinib