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...
| Autores: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| 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 |
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oai:gredos.usal.es:10366/169127 |
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| dc.title.none.fl_str_mv |
The src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial model of lung cancer brain metastasis in mice |
| title |
The src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial model of lung cancer brain metastasis in mice |
| spellingShingle |
The src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial model of lung cancer brain metastasis in mice Cerveró García, Pilar Brain metastasis lung cancer CSCs Src Connexin 3201.01 Oncología 3207.03 Carcinogénesis 3207.07 Patología Experimental |
| title_short |
The src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial model of lung cancer brain metastasis in mice |
| title_full |
The src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial model of lung cancer brain metastasis in mice |
| title_fullStr |
The src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial model of lung cancer brain metastasis in mice |
| title_full_unstemmed |
The src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial model of lung cancer brain metastasis in mice |
| title_sort |
The src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial model of lung cancer brain metastasis in mice |
| dc.creator.none.fl_str_mv |
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 |
| author |
Cerveró García, Pilar |
| author_facet |
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 |
| author_role |
author |
| author2 |
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 |
| author2_role |
author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Brain metastasis lung cancer CSCs Src Connexin 3201.01 Oncología 3207.03 Carcinogénesis 3207.07 Patología Experimental |
| topic |
Brain metastasis lung cancer CSCs Src Connexin 3201.01 Oncología 3207.03 Carcinogénesis 3207.07 Patología Experimental |
| description |
[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. |
| publishDate |
2026 |
| dc.date.none.fl_str_mv |
2026 2026 2026 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion |
| format |
article |
| status_str |
acceptedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10366/169127 |
| url |
http://hdl.handle.net/10366/169127 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
SA125P20 SA212P24 CLU2023-1-01 PID2021-128549OB-I00 MCIN/AEI/ 10.13039/501100011033 PDC2022-133652-I00 PID2024-161871OB-I00 MCIN/AEI/ 10.13039/501100011033 C15966/A24375 C16420/A18066 RYC2020-029435-I |
| dc.rights.none.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
Oxford University Press |
| publisher.none.fl_str_mv |
Oxford University Press |
| dc.source.none.fl_str_mv |
reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca instname:Universidad de Salamanca (USAL) |
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Universidad de Salamanca (USAL) |
| reponame_str |
GREDOS. Repositorio Institucional de la Universidad de Salamanca |
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GREDOS. Repositorio Institucional de la Universidad de Salamanca |
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| _version_ |
1869404099728900096 |
| spelling |
The src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial model of lung cancer brain metastasis in miceCerveró García, PilarJiménez Madrona, EnriqueÁlvarez Vázquez, AndreaFlores Hernández, RaquelGarcía Vicente, LauraGarcía Guerrero, LauraAlonso Amador, Juan JoséGonzález Sánchez, RaúlOllauri Ibáñez, ClaudiaPaniagua Sancho, MaríaTalaverón Aguilocho, RocíoRodrigues Teixeira, TelmoMartín Guerrero, Sandra M.Casado, PedroRajeeve, VinothiniShields, TommyHijazi Vega, MaruanCutillas, Pedro RJaraíz Rodríguez, MyriamTabernero Urbieta, María AránzazuBrain metastasislung cancerCSCsSrcConnexin3201.01 Oncología3207.03 Carcinogénesis3207.07 Patología Experimental[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.This research was funded by Junta de Castilla y León, FEDER SA125P20, SA212P24, CLU2023-1-01 (A.T.), the grant FEDER PID2021-128549OB-I00 (A.T.) funded by MCIN/AEI/ 10.13039/501100011033 and “ERDF A way of making Europe,” the grant PDC2022-133652-I00 (A.T.) and PID2024-161871OB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and “European Union Next Generation EU/PRTR”, the Cancer Research UK Programme Grant C15966/A24375 and C16420/A18066 (P.R.-C) and Blood Cancer UK grant 20008 (P.R.-C). P.C.G., A.Á.-V. and R.F.-H. received predoctoral fellowships from Junta de Castilla y León. L.G.-V. and E.J.-M. received a FPU predoctoral fellowship from MICIU. C.O.-I. and M.P.-S. received postdoctoral fellowships from Junta de Castilla y León. R.T. received a postdoctoral fellowship from Asociación Española Contra el Cáncer (AECC). P.C.-G and A.Á.-V. were also supported by EMBO Scientific Exchange Grants (#10334 and #9668). M.H. was supported by Ramón y Cajal fellowships from MICIU/AEI (RYC2020-029435-I). M.J-R. was supported by Usal4excellence European Union's Marie Skłodowska-Curie Actions (MSCA).Oxford University Press202620262026info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10366/169127reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)InglésSA125P20SA212P24CLU2023-1-01PID2021-128549OB-I00MCIN/AEI/ 10.13039/501100011033PDC2022-133652-I00PID2024-161871OB-I00MCIN/AEI/ 10.13039/501100011033C15966/A24375C16420/A18066RYC2020-029435-IAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1691272026-06-07T06:28:51Z |
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15.81155 |