Abstract PR05: A novel kinase inhibitor for B-catenin mutant hepatocellular carcinoma

Abstract

Abstract Purpose: We recently developed a chemical strategy for the diversification and disease-specific improvement of tool and FDA-approved kinase inhibitors, and sought to use this strategy for genotype-specific drug discovery in hepatocellular carcinoma (HCC). Experimental Procedures: Primary and murine-derived HCC organoids were used for drug screening. Expansive multiomic (phosphoproteomics, RNAseq, and ChIPseq) and target engagement analyses were used in combination with in vitro rescue and in vivo efficacy experiments. Data Summary: Currently there are few personalized therapeutic approaches for advanced HCC, which is a leading cause of cancer-related deaths worldwide. b-catenin (CTNNB1)-mutated HCC represents 30% of the disease and is a subset of Wnt-driven tumors particularly unresponsive to current therapies. Using focused chemical libraries derived from clinical multi-kinase inhibitor scaffolds, we screened HCC organoids to identify a CTNNB1-mutant selective small molecule that we dub WNTinib. WNTinib retained exquisite selectivity in human and murine models expressing oncogenic b-catenin, including patient samples. Our multidisciplinary approach revealed that WNTinib inhibits KIT/MAPK signaling at multiple nodes. Moreover, we demonstrate that lack of direct engagement on BRAF and p38a/b kinases differentiates WNTinib from existing clinical kinase inhibitors, is necessary to avoid compensatory feedback signaling, and thereby provides a durable and selective transcriptional block of mutant b-catenin and Wnt targets through re-activation of cytoplasmic enhancer of zest homolog 2 (EZH2). Finally, we demonstrate that the unique mechanism of WNTinib provides superior activity compared to clinical therapies in vivo, including in drug-resistant models of mutant b-catenin HCC. Conclusion: Our studies identify a novel inhibitor of the Wnt pathway and uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index. Our study also provides the rationale to explore WNTinib in proof-of-concept trials with enriched CTNNB1- mutant advanced HCC patients. Citation Format: Alexander Rialdi, Mary Duffy, Alex Scopton, Amaia Lujambio, Arvin Dar, Ernesto Guccione. A novel kinase inhibitor for B-catenin mutant hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PR05.