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Cancer Discov. 2016 Oct;6(10):1148-1165. Epub 2016 Aug 30.

Integrin-α10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma.

Author information

1
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.
2
Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
7
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.
8
Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan.
9
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.

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.

SIGNIFICANCE:

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.

PMID:
27577794
PMCID:
PMC5050162
DOI:
10.1158/2159-8290.CD-15-1481
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors disclose no potential conflicts of interest

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