Integrated molecular characterization of patient-derived models reveals therapeutic strategies for treating CIC-DUX4 sarcoma.

Capicua–double homeobox 4 (CIC-DUX4) rearranged sarcomas (CDSs) are extremely rare, highly aggressive primary sarcomas that represent a major therapeutic challenge. To identify selective therapeutic targets of CDS, we performed RNA sequencing of primary tumor samples from patients, patient-derived xenografts (PDXs) and PDX-derived cell lines and we highlighted an HMGA2/IGF2BPs/IGF2/IGF1R/AKT-mTOR axis that characterizes CDS. This highly active axis confers to CDSs sensitivity to both trabectedin, which prevents HMGA proteins from binding to IGF2BP2/3 promoters, and PI3K/mTOR inhibitor NVP-BEZ235 (dactolisib). Combined treatments with trabectedin and NVP-BEZ235 completely abolish the activation of the IGF2/IGF1R/AKT/mTOR axis and the in vivo growth of CDS tumors. The development of representative PDXs and PDX-derived cell lines models has helped to identify the unique sensitivities of CDS towards AKT/mTOR inhibitors and trabectedin, revealing a mechanism-based therapeutic strategy to fight this lethal cancer. This study aims to identify a specific transcriptional signature that characterizes CDS in order to highlight selective therapeutic targets. For this goal we performed RNA-seq on four CDS and four EWS tumor samples along with PDXs, and corresponding cell lines. GSEA and leading edge analysis revealed a selective gene expression signature and molecular dependence of CDS on an oncogenic axis, whose functional relevance was assessed in PDXs and corresponding cell lines. These models presented a high correlation score with their original tumors based on gene expression profile, and maintain the phenotypic characteristics assessed by morphological and immunohistochemistry analysis. We tested the feasibility of CDS-derived PDXs and CDS PDX-derived cell lines to determine disease-specific pharmacological vulnerabilities and their usefulness to prioritize actionable drug targets in a timely manner. In particular, we tested their in vitro and in vivo chemosensitivity to two chemicals compounds, trabectedin and/or NVP-BEZ235 (alone or in combination), which target genes of the oncogenic axis that characterizes CDS, to offer a rationale for disease-driven treatments.