FAK inhibition abrogates the malignant phenotype in aggressive pediatric renal tumors.
Despite the tremendous advances in the treatment of childhood kidney tumors, there remain subsets of pediatric renal tumors that continue to pose a therapeutic challenge, mainly malignant rhabdoid kidney tumors and nonosseous renal Ewing sarcoma. Children with advanced, metastatic, or relapsed disease have a poor disease-free survival rate. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult renal cellular carcinoma, leading to the hypothesis that FAK contributes to pediatric kidney tumors and would affect cellular survival. In the current study, FAK was present and phosphorylated in pediatric kidney tumor specimens. Moreover, the effects of FAK inhibition upon G401 and SK-NEP-1 cell lines were examined using a number of parallel approaches to block FAK, including RNA interference and small-molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion and migration, and increased apoptosis. Furthermore, small-molecule inhibition of FAK led to decreased SK-NEP-1 xenograft growth in vivo. These data deepen the knowledge of the tumorigenic process in pediatric renal tumors, and provide desperately needed therapeutic strategies and targets for these rare, but difficult to treat, malignancies.


CONCLUSIONS
This study provides a fundamental understanding of tumorigenesis in difficult to treat renal tumors and provides an impetus for new avenues of research and potential for novel, targeted therapies.
University of Alabama at Birmingham, 1600 7th Avenue South, Lowder, Room 300, Birmingham, AL 35233. elizabeth.beierle@childrensal.org.
Michael L
ML
Megison
Lauren A
LA
Gillory
Jerry E
JE
Stewart
Hugh C
HC
Nabers
Elizabeth
E
Mrozcek-Musulman
Elizabeth A
EA
Beierle
D000293:Adolescent; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000628:therapy*; D008819:Mice, Nude; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011897:Random Allocation; D012512:Sarcoma, Ewing / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
C539551:1,2,4,5-benzenetetraamine; D000814:Aniline Compounds; D000911:Antibodies, Monoclonal; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human