Targeted KRASG12V Degradation In Vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis.

Targeted KRASG12V degradation causes rapid lung adenocarcinoma regression in mice, but resistance develops due to dysregulated proteolysis, highlighting a new therapeutic avenue.

• Why it matters: Understanding how KRAS degradation impacts tumor biology and resistance mechanisms is crucial for improving treatments for lung adenocarcinoma, especially given limitations of current KRAS inhibitors.
• What they did: Researchers used a preclinical LUAD mouse model to induce KRASG12V degradation via PROTACs, analyzing tumor response, microenvironment changes, and resistance pathways through molecular and histological methods.
• The result: KRAS degradation led to swift tumor shrinkage driven by cancer cell-autonomous effects, but resistance emerged from proteolysis machinery dysregulation, informing future strategies to sustain therapeutic responses.