The src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial model of lung cancer brain metastasis in mice

[EN] Background: TAT-Cx43266-283 is a novel Src inhibitor, which has shown noteworthy antitumor effects in preclinical models of glioblastoma. Because Src plays a pivotal role in several tumor types, including lung cancer brain metastasis derived from non-small cell lung cancer (NSCLC) cells, we inv...

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Detalles Bibliográficos
Autores: Cerveró García, Pilar, Jiménez Madrona, Enrique, Álvarez Vázquez, Andrea, Flores Hernández, Raquel, García Vicente, Laura, García Guerrero, Laura, Alonso Amador, Juan José, González Sánchez, Raúl, Ollauri Ibáñez, Claudia, Paniagua Sancho, María, Talaverón Aguilocho, Rocío, Rodrigues Teixeira, Telmo, Martín Guerrero, Sandra M., Casado, Pedro, Rajeeve, Vinothini, Shields, Tommy, Hijazi Vega, Maruan, Cutillas, Pedro R, Jaraíz Rodríguez, Myriam, Tabernero Urbieta, María Aránzazu
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2026
País:España
Institución:Universidad de Salamanca (USAL)
Repositorio:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/169127
Acceso en línea:http://hdl.handle.net/10366/169127
Access Level:acceso abierto
Palabra clave:Brain metastasis
lung cancer
CSCs
Src
Connexin
3201.01 Oncología
3207.03 Carcinogénesis
3207.07 Patología Experimental
Descripción
Sumario:[EN] Background: TAT-Cx43266-283 is a novel Src inhibitor, which has shown noteworthy antitumor effects in preclinical models of glioblastoma. Because Src plays a pivotal role in several tumor types, including lung cancer brain metastasis derived from non-small cell lung cancer (NSCLC) cells, we investigated the effect of TAT-Cx43266-283 in NSCLC-derived brain metastasis, a disease of unmet clinical need. Methods: The effect of TAT-Cx43266-283 was studied in Lewis Lung Carcinoma (LLC), LSZ4, A549 and H441 NSCLC cells. The non-adherent stem-like LLC cells (LLC-CSCs) were intracranially implanted in immunocompetent mice to study the effect of TAT-Cx43266-283 in vivo. Phosphoproteomic analysis was employed to identify signaling pathways affected by TATCx43266-283, and the most prominent were validated by Western blot and immunohistochemistry. Datasets of human NSCLC adenocarcinoma were also analyzed. Results: TAT-Cx43266-283 significantly reduced LLC-CSCs viability and increased the survival of mice bearing brain tumors derived from these cells. Phosphoproteomic analysis identified MEK and ERK as key effectors of this treatment. TAT-Cx43266-283 induced apoptosis, impaired cytoskeletal dynamics and disrupted tumor vascularization. Patient datasets revealed that the targets of TAT-Cx43266-283 were significantly enriched in KRAS-altered lung tumors. Functional validation in several human and mouse KRAS-mutated non-adherent NSCLC cells confirmed that TAT-Cx43266-283 reduced their growth and invasiveness. Conclusions: Our results suggest that TAT-Cx43266-283 is a promising antitumor drug for lung cancer brain metastasis, as judged by the dual inhibition of Src and the MEK-ERK pathway in KRAS-mutated NSCLC. This study opens new avenues for exploring TAT-Cx43266-283 in other tumor types driven by these molecular alterations.

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