Abstract 4445: Super-enhancers reorganization controls re-sensitization of oxaliplatin-resistant FBXW7-mutated colorectal cancer

Abstract The resistance of cancer to therapies remains an unresolved issue. It may result from tumor evolution, which is characterized by epigenetic plasticity and large-scale chromatin remodeling. Catalytically inactive class IIa HDACs (HDAC4, HDAC5, HDAC7, HDAC9) control the targeted recruitment of chromatin remodeling complexes, making them attractive therapeutic targets in oncology. Recently, we have described the role of HDAC4 in monitoring the assembly of the end resection complex involved in homologous recombination (HR) repair. In cells defective for HR repair, HDAC4 is proteasomally degraded. Here, through in silico and in vitro screenings we identified FBXW7 as the E3 ligase involved in proteasomal degradation of HDAC4, and its role was confirmed by means of ubiquitin co-immunoprecipitation experiments and in vitro ubiquitylation assays. FBXW7 is a tumor suppressor gene encoding the substrate recognition component of an SCF ubiquitin ligase complex. It is one of the most frequently mutated genes in colorectal cancer (CRC), and loss of function of FBXW7 has been reported to induce resistance to chemotherapeutic agents such as oxaliplatin (OxPt), which is commonly used in adjuvant therapy for CRC. We confirmed that FBXW7-/- CRC cells were resistant to OxPt treatment and HDAC4 was not degraded under these conditions. Silencing or forced degradation of HDAC4 using a PROTAC-based compound restored OxPt sensitivity in FBXW7-mutated CRC cells, in patient-derived organoids (PDOs) and in a xenograft model in mice. By evaluating the transcriptomic landscape and super-enhancer (SE) repertoire status in FBXW7-mutated PDOs, we demonstrated the relevance of epigenetic resetting in controlling OxPt resistance. In particular, forced downregulation of HDAC4 resulted in dramatic loss of SEs in FBXW7-deficient tumors and restoration of certain SEs found in OxPt-sensitive tumors. Furthermore, patient profiling based on the epigenetic state of SEs controlled by HDAC4 identified a priori CRC patients resistant to OxPt. This study supports HDAC4 as a key mediator of OxPt resistance in FBXW7-mutated CRC and highlights the remodeling of a well-defined repertoire of SEs as part of the process of successful re-sensitization. Citation Format: Vanessa Tolotto, Nicolò Gualandi, Raffaella Picco, Ylenia Cortolezzis, Francesca D'Este, Monica Colitti, Wayne W. Hancock, Claudio Brancolini, Luigi Xodo, Eros Di Giorgio. Super-enhancers reorganization controls re-sensitization of oxaliplatin-resistant FBXW7-mutated colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4445.