title: Integrin-α10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma.
abstract: Myxofibrosarcoma is a common mesenchymal malignancy with complex genomics and heterogeneous clinical outcomes. Through gene-expression profiling of 64 primary high-grade myxofibrosarcomas, we defined an expression signature associated with clinical outcome. The gene most significantly associated with disease-specific death and distant metastasis was ITGA10 (integrin-α10). Functional studies revealed that myxofibrosarcoma cells strongly depended on integrin-α10, whereas normal mesenchymal cells did not. Integrin-α10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had antitumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-α10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease.
  
  
  
  Identifying the molecular pathogenesis for myxofibrosarcoma progression has proven challenging given the highly complex genomic alterations in this tumor type. We found that integrin-α10 promotes tumor cell survival through activation of TRIO-RAC-RICTOR-mTOR signaling, and that inhibitors of RAC and mTOR have antitumor effects in vivo, thus identifying a potential treatment strategy for patients with high-risk myxofibrosarcoma. Cancer Discov; 6(10); 1148-65. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1069.
authors: Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. singers@mskcc.org t-okada@ski.mskcc.org.
authors: Tomoyo
authors: T
authors: Okada
authors: Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Ann Y
authors: AY
authors: Lee
authors: Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Li-Xuan
authors: LX
authors: Qin
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Narasimhan
authors: N
authors: Agaram
authors: Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Takahiro
authors: T
authors: Mimae
authors: Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Yawei
authors: Y
authors: Shen
authors: Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Rachael
authors: R
authors: O'Connor
authors: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Miguel A
authors: MA
authors: López-Lago
authors: Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Amanda
authors: A
authors: Craig
authors: Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Martin L
authors: ML
authors: Miller
authors: Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Phaedra
authors: P
authors: Agius
authors: Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Evan
authors: E
authors: Molinelli
authors: Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Nicholas D
authors: ND
authors: Socci
authors: Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Surgery, Weill Cornell Medical College, New York, New York.
authors: Aimee M
authors: AM
authors: Crago
authors: Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan.
authors: Fumi
authors: F
authors: Shima
authors: Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Chris
authors: C
authors: Sander
authors: Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Surgery, Weill Cornell Medical College, New York, New York. singers@mskcc.org t-okada@ski.mskcc.org.
authors: Samuel
authors: S
authors: Singer
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D005354:Fibrosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D015854:Up-Regulation; D020744:rac GTP-Binding Proteins / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D039001:Integrin alpha Chains; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C406210:integrin alpha 10; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C099628:TRIO protein, human; D020744:rac GTP-Binding Proteins