CIC-Rearranged Sarcomas: An Intriguing Entity That May Lead the Way to the Comprehension of More Common Cancers

SIMPLE SUMMARY: In this review, we aim to summarize the current clinical and biological knowledge for patients affected by a rare soft-tissue sarcoma, the CIC-rearranged sarcoma, to highlight novel treatment perspectives and to remark the need of innovative clinical trials. CIC-rearranged sarcoma is still entrapped in unspecific therapeutic regimens which result in poor prognosis and high incidence of recurrence. The comprehension of the biology of this tumor and the exact mechanisms of action of its molecular markers are mandatory to identify specific cancer vulnerabilities to exploit for therapy. Clinical research for rare tumors is complicated by the difficulties in patients’ recruitment and the lack of interest of Big Pharma in the development of new treatments. An intriguing perspective is given by the identification of CIC and its targets dysregulation as a common determinant of different tumor types, which might fasten the development of effective mechanism-based therapies. ABSTRACT: Capicua transcriptional repressor (CIC)-rearranged sarcoma, belonging to the undifferentiated round cells sarcoma family, is characterized by high metastatic rate and poor chemo response. CIC sarcoma represents a new entity harboring the recurrent chromosomal translocation between CIC and, in most of the cases, DUX4. CIC-DUX4 imposes a CIC-specific transcriptional signature, which drives cell transformation, proliferation, and migration. While the discovery of the fusion represented the first evidence of a role of CIC in cancer, a complete comprehension of CIC-rearranged activity is still required before providing new potential avenues for therapy. To date, a specific and effective treatment for CIC sarcoma has yet to be defined. In this review, we initially highlight the clinical features and pathogenesis of CIC-rearranged sarcomas along with current therapeutic approaches and then focus on the specific oncogenic mechanisms driven by the CIC-rearrangement. We discuss novel therapeutic options evoked by the aberrant relations of CIC-DUX4 with the IGF system, DUSP6, P300/CBP, and CCNE1. We also discuss how different mutations involving CIC might converge on a common upregulation of CIC-target genes across human cancers. A deeper understanding of the oncogenic mechanisms driven by the chimera CIC-DUX4 might provide novel therapeutic opportunities with a general impact in cancer.