PDGF receptor alpha is an alternative mediator of rapamycin-induced akt activation: Implications for combination targeted therapy of synovial sarcoma Journal Article

   

Authors:	Ho, A. L.; Vasudeva, S. D.; Lae, M.; Saito, T.; Barbashina, V.; Antonescu, C. R.; Ladanyi, M.; Schwartz, G. K.
Article Title:	PDGF receptor alpha is an alternative mediator of rapamycin-induced akt activation: Implications for combination targeted therapy of synovial sarcoma
Abstract:	Akt activation by the IGF-1 receptor (IGF-1R) has been posited to be a mechanism of intrinsic resistance to mTORC1 inhibitors (rapalogues) for sarcomas. Here we show that rapamycin-induced phosphorylation of Akt can occur in an IGF-1R-independent manner. Analysis of synovial sarcoma cell lines showed that either IGF-1R or the PDGF receptor alpha (PDGFRA) can mediate intrinsic resistance to rapamycin. Repressing expression of PDGFRA or inhibiting its kinase activity in synovial sarcoma cells blocked rapamycin-induced phosphorylation of Akt and decreased tumor cell viability. Expression profiling of clinical tumor samples revealed that PDGFRA was the most highly expressed kinase gene among several sarcoma disease subtypes, suggesting that PDGFRA may be uniquely significant for synovial sarcomas. Tumor biopsy analyses from a synovial sarcoma patient treated with the mTORC1 inhibitor everolimus and PDGFRA inhibitor imatinib mesylate confirmed that this drug combination can impact both mTORC1 and Akt signals in vivo. Together, our findings define mechanistic variations in the intrinsic resistance of synovial sarcomas to rapamycin and suggest therapeutic strategies to address them. ©2012 AACR.
Keywords:	signal transduction; protein kinase b; controlled study; human tissue; human cell; major clinical study; antineoplastic agents; proteins; animals; mice; cell viability; imatinib; platelet derived growth factor alpha receptor; gene overexpression; receptor, platelet-derived growth factor alpha; gene expression; gene expression profiling; tumor biopsy; in vivo study; transcription, genetic; cancer cell culture; enzyme activation; enzyme activity; cell line, tumor; pyrimidines; phosphorylation; somatomedin c receptor; gene expression regulation, neoplastic; antibodies, monoclonal; enzyme phosphorylation; enzyme regulation; proto-oncogene proteins c-akt; oncogene proteins, fusion; piperazines; synovial sarcoma; sarcoma, synovial; drug sensitivity; everolimus; rapamycin; sirolimus; sample; sarcoma cell; molecular targeted therapy; pharmacological blocking; phosphatidylinositol 3-kinases
Journal Title:	Cancer Research
Volume:	72
Issue:	17
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2012-09-01
Start Page:	4515
End Page:	4525
Language:	English
DOI:	10.1158/0008-5472.can-12-1319
PROVIDER:	scopus
PMCID:	PMC3432680
PUBMED:	22787122
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84865722534&partnerID=40&md5=896d46ff619085892e50da26df1bba24
Notes:	--- - "Export Date: 1 October 2012" - "CODEN: CNREA" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/33754