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

Cancer Discov. 2016 Oct;6(10):1148-1165. doi: 10.1158/2159-8290.CD-15-1481. Epub 2016 Aug 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • Up-Regulation
  • rac GTP-Binding Proteins / genetics*

Substances

  • Carrier Proteins
  • Guanine Nucleotide Exchange Factors
  • Integrin alpha Chains
  • RICTOR protein, human
  • Rapamycin-Insensitive Companion of mTOR Protein
  • integrin alpha 10
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • TRIO protein, human
  • rac GTP-Binding Proteins