Reference Detail

Ref Type Journal Article
PMID (27577794)
Authors Okada T, Lee AY, Qin LX, Agaram N, Mimae T, Shen Y, O'Connor R, López-Lago MA, Craig A, Miller ML, Agius P, Molinelli E, Socci ND, Crago AM, Shima F, Sander C, Singer S
Title Integrin-α10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma.
Journal Cancer discovery
Vol 6
Issue 10
Date 2016 Oct
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown malignant fibroxanthoma not applicable EHop-016 + IPA-3 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of EHop-016 and IPA-3 resulted in increased apoptosis and reduced growth of a myxofibrosarcoma cell line in culture compared to either agent alone (PMID: 27577794). 27577794
Unknown unknown malignant fibroxanthoma not applicable EHop-016 Preclinical - Cell line xenograft Actionable In a preclinical study, EHop-016 inhibited AKT activation and increased apoptosis and reduced growth of a myxofibrosarcoma cell line in culture, and inhibited tumor growth in xenograft models (PMID: 27577794). 27577794
Unknown unknown malignant fibroxanthoma not applicable Sapanisertib Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with Sapanisertib (MLN0128) resulted in growth suppression and arrest in a myxofibrosarcoma cell line in culture, and inhibited tumor growth in myxofibrosarcoma cell line xenograft models (PMID: 27577794). 27577794
Unknown unknown malignant fibroxanthoma not applicable EHop-016 + MLN0128 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of EHop-016 and Sapanisertib (MLN0128) resulted in increased apoptosis and reduced growth of a myxofibrosarcoma cell line in culture, and resulted in greater tumor growth inhibition in myxofibrosarcoma cell line xenograft models compared to either agent alone (PMID: 27577794). 27577794
Unknown unknown malignant fibroxanthoma not applicable IPA-3 Preclinical - Cell culture Actionable In a preclinical study, IPA-3 increased apoptosis and inhibited growth of a myxofibrosarcoma cell line in culture (PMID: 27577794). 27577794