CDK inhibitors are a promising treatment for malignant melanoma with CIC mutation

Abstract

Abstract Background: Capicua (CIC) is a highly conserved high mobility group protein repressor that is mainly involved in mammalian development and homeostasis. Recent findings have shown that CIC mutation can lead to tumor progression and metastasis in various cancers, while the effect of CIC mutation on melanoma has not been reported. This study investigated the clinical and biological significance of CIC in melanoma. Methods: This study reviewed the treatment of a 34-year-old Chinese female patient with malignant melanoma (MM) harboring CIC mutation. We further analyzed the mutational status, gene expression differences, and drug resistance of CIC from TCGA and GDSC databases. Simultaneously, we conducted A375, Hs294T cell proliferation, migration assays, Western blot assays for the downstream target gene expression after CIC knockdown, and in vivo animal experiments to analyze the effect of CIC expression on MM. Furthermore, CCK-8 and Clone-formation assays were conducted to assess the effect of the CDK inhibitor Dinaciclib on the proliferation of cells with decreased CIC expression. Results: Here, we reported a metastatic MM harboring CIC mutation was effective with Lenvatinib combined with Crizotinib for the first time, while chemotherapy, cytokines, and immunotherapy were ineffective. In vitro and in vivo experiments demonstrated silencing CIC gene expression profoundly augmented cell proliferation and metastasis, while concurrently upregulating MMP-9 expression and stimulating EMT. Moreover, the CDK inhibitor Dinaciclib had a pronounced inhibitory effect on MM cells, regardless of CIC gene knockdown. Conclusion: CIC gene knockdown boosts MM growth and metastasis and CDK inhibitors hold promise for treating malignant melanoma.