2026-08-06T12:17:01Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/274982026-06-03T00:17:19Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
de-la-Puente-Ovejero, Laura
author
Fernández-Rodríguez, Ana
author
Francoz, Sarah
author
Aizpurua, Gonzalo
author
Lomba-Riego, Lucía
author
Drosten, Matthias
author
Guerra, Carmen
author
Musteanu, Mónica
author
Barbacid, Mariano
author
García-Alonso, Sara
funder
madrid
funder
Comunidad de Madrid (España)
funder
Ministerio de Ciencia e Innovación (España)
funder
Fundación La Caixa
funder
Centro de Investigación Biomédica en Red - CIBERONC (Cáncer)
funder
Agencia Estatal de Investigación (España)
2026-06-02T11:58:32Z
2026-06-02T11:58:32Z
2026
PLoS One . 2026 Feb 6;21(2):e0341778.
PLos One
41650121
https://hdl.handle.net/20.500.12105/27498
KRAS-mutant lung adenocarcinoma remains without effective targeted therapies for most patients, particularly those with non-G12C alleles or resistance to KRASG12C inhibitors. RAF1 is essential for KRAS-driven tumor maintenance through kinase-independent survival functions, making it an attractive candidate for targeted protein degradation. However, the therapeutic impact and safety of co-targeting RAF1 with related kinases remain unclear.We used dual-recombinase genetically engineered mouse models of Kras+/G12V;Trp53-/- lung cancer to evaluate the effects of Raf1 ablation alone or in combination with Araf, Egfr, or Ddr1. Lung tumors were initiated by intranasal Ad5-CMV-FLPo delivery and allowed to reach CT-detectable size before inducing systemic gene deletion via tamoxifen-activated CreERT2. Tumor burden was monitored by longitudinal CT imaging and classified using RECIST-like criteria. Toxicity was assessed by body weight monitoring, histopathology of major organs, and survival analysis.Raf1 deletion induced robust tumor regression within two months, in more than 60% of lesions. Araf ablation alone or combined with Raf1 did not affect tumor initiation, progression, or regression rates. Similarly, neither genetic nor pharmacological EGFR inhibition (afatinib) improved responses to Raf1 ablation. Ddr1 co-deletion also failed to enhance therapeutic efficacy and slightly reduced response rates. None of the dual-targeting strategies increased systemic toxicity.RAF1 is a key, non-redundant vulnerability in KRAS-driven lung adenocarcinoma. Co-targeting ARAF, EGFR, or DDR1 provides no additional therapeutic benefit in established disease. The absence of adverse effects from ARAF co-deletion suggests that RAF1 degraders with partial cross-activity towards ARAF are likely to be safe. These findings provide a strong preclinical rationale for developing RAF1-targeted degradation as a monotherapy for these malignancies.
eng
K-RAS ONCOGENE
A-RAF
B-RAF
PROTEIN-KINASE
APOPTOSIS
MICE
REGRESSION
MUTATIONS
LETHALITY
RAF1 as a standalone therapeutic target in KRAS-driven lung adenocarcinoma: No added efficacy from co-targeting ARAF, EGFR, or DDR1.
research article
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URL
https://repisalud.isciii.es/bitstreams/f2478989-a23a-4e18-9616-98f3d1ffe091/download
File
MD5
ab22898675427a8340cd7626c1a97510
18259186
application/pdf
RAF1asatandalone_2026.pdf