PDGF receptor alpha is an alternative mediator of rapamycin-induced Akt activation: implications for combination targeted therapy of synovial sarcoma.
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.
Laboratory of New Drug Development, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, NY 10065, USA. hoa@mskcc.org
Alan L
AL
Ho
Shyamprasad Deraje
SD
Vasudeva
Marick
M
Laé
Tsuyoshi
T
Saito
Violetta
V
Barbashina
Cristina R
CR
Antonescu
Marc
M
Ladanyi
Gary K
GK
Schwartz
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013584:Sarcoma, Synovial / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001549:Benzamides; D000068877:Imatinib Mesylate; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C116512:SYT-SSX fusion protein; C551399:teprotumumab