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.

• Authors: Alan L Ho, Shyamprasad Deraje Vasudeva, Marick Laé, Tsuyoshi Saito, Violetta Barbashina, Cristina R Antonescu, Marc Ladanyi, Gary K Schwartz
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 17 Pg. 4515-25 (Sep 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22787122 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2012 AACR.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Benzamides
• Multiprotein Complexes
• Oncogene Proteins, Fusion
• Piperazines
• Proteins
• Pyrimidines
• SYT-SSX fusion protein
• Imatinib Mesylate
• Receptor, Platelet-Derived Growth Factor alpha
• Mechanistic Target of Rapamycin Complex 1
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Sirolimus
• teprotumumab

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacology)
• Benzamides
• Cell Line, Tumor
• Enzyme Activation (drug effects)
• Gene Expression Regulation, Neoplastic
• Humans
• Imatinib Mesylate
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Molecular Targeted Therapy
• Multiprotein Complexes
• Oncogene Proteins, Fusion (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Piperazines (pharmacology)
• Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrimidines (pharmacology)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, genetics, metabolism)
• Sarcoma, Synovial (drug therapy, genetics, metabolism)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases
• Transcription, Genetic