Cancer discovery, 2016-10, Vol.6 (10), p.1148-1165
2016
Details
- Autor(en) / Beteiligte
- Titel
- Integrin-α10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma
- Ist Teil von
- Cancer discovery, 2016-10, Vol.6 (10), p.1148-1165
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2159-8274eISSN: 2159-8290DOI: 10.1158/2159-8290.cd-15-1481Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5050162
- Format
- –
- Schlagworte
- Animals, Carrier Proteins - genetics, Cell Line, Tumor, Fibrosarcoma - drug therapy, Fibrosarcoma - genetics, Fibrosarcoma - metabolism, Fibrosarcoma - pathology, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Guanine Nucleotide Exchange Factors - genetics, Humans, Integrin alpha Chains - genetics, Integrin alpha Chains - metabolism, Mice, Molecular Targeted Therapy, Neoplasm Grading, Neoplasm Transplantation, Protein Serine-Threonine Kinases - genetics, Proto-Oncogene Proteins c-akt - genetics, rac GTP-Binding Proteins - genetics, Rapamycin-Insensitive Companion of mTOR Protein, Signal Transduction, TOR Serine-Threonine Kinases - genetics, Up-Regulation