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

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.