Targeting Cancer Through Modifications and Metabolism

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

The goal of this project is to characterize and control novel modification-based regulatory mechanisms that drive altered gene activity in cancer. Our research seeks to expand beyond the traditional focus on phosphorylation to target the hundreds of chemically distinct modifications that tumors exploit. Over the past year, we have made substantial progress, which we group here into three Aims. 1. Next-Generation Histone Acetyltransferase Inhibitors. Targeting transcription factors through histone acetyltransferase (HAT) activity represents a promising strategy for cancer therapy. As these agents progress into clinical trials, understanding their selectivity and tailoring their therapeutic window becomes critical. To facilitate this, we carried out a comprehensive comparative analysis of MYST acetyltransferase inhibitor selectivity (Chen et al., bioRxiv 2025). Our studies indicate that commercial MYST inhibitors hierarchically engage targets in the order KAT6A/B > KAT7 >> KAT8, revealed orders-of-magnitude differences in the potency of these agents, and defined a set of specific acetylated histone biomarkers that can be used for tracking individual HAT inhibition. These insights are being used to inform the dosing of clinical MYST HAT inhibitors and enable the rational exploration of dual KAT6/7 inhibition in cancer therapy. Our future work will focus on applying structure-activity insights gained from our studies of HAT inhibitors (Crawford et al., ACS Chem Biol, 2023) and degraders (Chen et al., JACS Au, 2024) to develop HAT inhibitors with increased therapeutic window and extend our methods to develop highly specific chemical probes of additional members of this enzyme family. 2. RNA acetylation as a cancer target. RNA modifications represent an untapped therapeutic modality for targeted regulation of dysregulated protein synthesis in cancer. To explore this strategy our group has taken a mechanism-first approach to advance the study of N4-acetylcytidine (ac4C), a modified nucleobase that embodies the potential and challenges of this research frontier (Gamage, Acc Chem Res 2024). To understand what individual ac4C sites do and how they contribute to disease we recently reported a strategy to selectively disrupt tRNA acetylation in vivo by knocking out the NAT10 adapter protein THUMPD1 (Gamage, Sci Adv 2025). Analysis of this model revealed that ac4C in tRNA serves a sentinel function, which when lost drives ribosome collisions and signaling cascades that are necessary for cells to adapt to stress. Notably, stress caused by loss of ac4C directly impairs the ability of circulating tumor cells to adapt to the pre-metastatic niche (Chen, Sci Adv 2025). Currently we are applying these models to dissect tRNA acetylation's role in cancer and development while leveraging NAT10 biochemistry and structural data (Zhou et al. bioRxiv 2024; Gamage et al. NAR 2025) for the design of chemical probes and potential anti-metastatic agents. 3. Uncovering Modification-Dependent Synthetic Lethalities: How do we target dysregulated modification profiles when they are driven by upstream deletion of a tumor suppressor, rather than a druggable enzyme? Here our group is leveraging our expertise in chemoproteomics and screening to identify modification-dependent synthetic lethalities. We have used HLRCC, a hereditary kidney cancer driven by fumarate hydratase (FH) loss and prevalent protein S-succination, as a testbed for our methods. Building on our studies of covalent fragments as synthetic lethal reagents in this cancer (Perez et al., ACS Chem Biol 2022) we screened a small library of annotated inhibitors and identified NAD+ metabolism as a critical vulnerability in FH-deficient cancers (Najera, Mol Cancer Ther 2025). The therapeutic progression of these agents is being carried out by clinical collaborators at CCR, while our group is focused on developing these platforms so they may be extended to additional loss-of-function cancer contexts.