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Targeted KRAS(G12V) degradation elicits efficient and durable lung adenocarcinoma regression in vivo

ABSTRACT: Recent drug discovery breakthroughs led to the approval of KRASG12C inhibitors in lung adenocarcinoma (LUAD). Unfortunately, clinical responses remain limited due to rapid resistance onset. 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 KRAS degradation induces rapid tumor regression. Transcriptional and histological analyses revealed a substantial remodeling of the tumor microenvironment. Notably, the low resistance rate observed during long-term treatment stems from proteolysis machinery dysregulation rather than KRAS absence adaptation, indicating resistance mechanisms distinct from KRAS inhibition. Our findings highlight the therapeutic potential of KRAS degradation in LUAD, offering insights into cell-intrinsic and extrinsic mechanisms driving durable antitumor responses and supporting further clinical exploration.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung

DISEASE(S): Lung Adenocarcinoma

SUBMITTER: Marta Vilaseca

LAB HEAD: Marta Vilaseca

PROVIDER: PXD058734 | Pride | 2026-05-13

REPOSITORIES: Pride

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			Action	DRS
	0602_UniversalContaminants.fasta	Fasta
	4900_BB_34SM_R01_I11.raw	Raw
	4900_BB_34SM_R02_I19.raw	Raw
	4900_BB_34SM_R03_I06.raw	Raw
	4900_BB_429_R01_I09.raw	Raw

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