Abstract LT10: Recurrent FBXW7 Mutations Bypass Wnt/β-catenin Addiction in Cancer

Abstract

Abstract Inactivating mutations in RNF43 or gene fusions involving RSPO2/3 are potent activators of ligand-dependent Wnt signaling and drive multiple human cancers. Pharmacologically targeting the biogenesis of Wnt ligands, e.g., with PORCN inhibitors, is being investigated in clinical trials for treating RNF43-mutant/RSPO-fusion cancers. But, the therapeutic response is heterogeneous. Here we show that the tumor suppressor FBXW7 is frequently mutated in RNF43-mutant/RSPO-fusion tumors. Multiple RNF43-mutant/RSPO-fusion cancers harboring FBXW7 mutations show resistance to Wnt pathway blockade, while silencing FBXW7 by truncation or expressing a hotspot mutant in FBXW7-wildtype tumors leads to intrinsic drug resistance. Mechanistically, inactivation of FBXW7, the substrate recognition component of a SCF E3 ubiquitin ligase complex, stabilizes multiple oncoproteins especially Cyclin E and MYC, and antagonizes the cytostatic effect of Wnt inhibitors in these cancers. Moreover, although FBXW7 mutations do not mitigate β-catenin degradation upon Wnt inhibition, FBXW7 mutants instead lose dependence on β-catenin signaling, accompanied by dedifferentiation and loss of lineage specificity. These FBXW7-mutant Wnt/β-catenin-independent tumors are susceptible to multi-CDK inhibition by dinaciclib that targets both cell cycle and transcription. In summary, this study identifies FBXW7 mutations as a mechanism of Wnt independence and drug resistance in RNF43-mutant/RSPO-fusion cancers and reveals the potential of treating these cancers with multi-CDK inhibitors. Citation Format: Zheng Zhong, David Virshup. Recurrent FBXW7 Mutations Bypass Wnt/β-catenin Addiction in Cancer [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT10.