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Targeted KRAS G12V degradation elicits efficient and durable lung adenocarcinoma regression in vivo [dTAG_expt3_RNAseq]

ABSTRACT: Recent drug discovery breakthroughs led to the approval of KRASG12C inhibitors in lung adenocarcinoma (LUAD). Unfortunately, clinical responses are often hampered by the rapid emergence of resistance. Proteolysis-targeting chimeras (PROTACs) have emerged as promising alternatives to traditional inhibition. However, there is limited mechanistic understanding of KRAS degradation in vivo. Here, we developed a preclinical LUAD mouse model and demonstrated that targeted oncogenic KRAS degradation induces rapid tumor regression primarily due to cancer cell-intrinsic mechanisms. Yet, transcriptional, histological, and immunophenotypic analyses revealed a substantial remodeling of the tumor microenvironment. Notably, disease relapse observed during prolongued degrader treatment stems from proteolysis machinery dysregulation, indicating resistance mechanisms distinct from those reported upon KRAS inhibition. Collectively, our findings highlight the therapeutic potential of KRAS degradation in LUAD, providing insights into both cell-intrinsic and -extrinsic mechanisms that accompany antitumor responses and support the continued clinical development of this approach.

ORGANISM(S): Mus musculus

PROVIDER: GSE326057 | GEO | 2026/05/14

REPOSITORIES: GEO

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Project description:KRAS, one of the most frequently mutated oncogenes in cancer, has long posed a formidable therapeutic challenge due to the difficulty of directly inhibiting its activity. A major breakthrough emerged with the development of covalent, allele- specific inhibitors targeting KRAS G12C , such as sotorasib. However, the clinical utility of these inhibitors is frequently limited by the rapid development of acquired resistance. Targeted protein degradation (TPD) has emerged as an effective approach with the potential to overcome drug resistance, but it has been mostly restricted to large-size PROTACs. In this study, we present the first small-molecule KRAS G12C degrader, DJX-A-KM, designed by integrating a simple acrylamide warhead into the hydrophilic moiety of the MRTX849 scaffold. DJX-A-KM induces rapid, robust, and sustained degradation of KRAS G12C in both cellular and animal models (DC50: 2 nM; Dmax: 98%; 60h durability), demonstrating superior pharmaceutical properties to PROTACs. Mechanistic investigations revealed that degradation is mediated by the ubiquitin-proteasome system, facilitated by covalent engagement with a new E3 ligase, FBXO28, at cysteine 98 through the acrylamide warhead. Antiproliferation assays demonstrated its potent inhibitory effects across multiple KRAS G12C -mutant cancer models, with in vivo studies confirming significant tumor growth suppression mediated by targeted KRAS G12C degradation. Notably, this chemical strategy extends beyond KRAS G12C , offering a blueprint for developing pan-KRAS degraders against a broader spectrum of KRAS mutations. To our knowledge, this study reports the first small-molecule degrader that recruits FBXO28 as an E3 ligase, employing a novel dual covalent strategy to achieve the highest targeted degradation of KRAS G12C thus far. Additionally, it represents the first small-molecule pan-KRAS degrader and provides a feasible approach for exploring new E3 ligases in targeted protein degradation applications.

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Targeted KRAS G12V degradation elicits efficient and durable lung adenocarcinoma regression in vivo [dTAG_expt3_RNAseq]

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