Effect of the Src inhibitor peptide TAT-Cx43266-283 in lung cancer brain metastasis models.

ABSTRACT: Background: TAT-Cx43266-283 is a novel inhibitor of Src, which has shown important antitumor effects in preclinical models of glioblastoma. Because Src plays a pivotal role in several tumors, including lung cancer and brain metastasis, in this study we investigated the effect of TAT-Cx43266-283 in lung cancer brain metastasis, an unmet clinical need. Methods: Cancer Stem Cells (CSCs) from the murine lung cancer cell line LLC, named LLC-CSCs, were isolated and used to study the effect of TAT-Cx43266-283 in vitro and to develop an in vivo model of lung cancer brain metastasis. Thus, in vivo models were carried out performing an intracranial implantation of LLC-CSCs in immunocompetent mice and the impact of TAT-Cx43266-283 in these models was assessed. A phosphoproteomic analysis was employed to identify signaling pathways affected by TAT-Cx43266-283, and the most prominent targets were validated by immunofluorescence or Western Blot. Results: We found that TAT-Cx43266-283 significantly reduced LLC-CSCs viability and increased the survival of immunocompetent mice bearing lung cancer derived-brain metastatic tumors. Phosphoproteomic analysis identified ERK as a key effector of TAT-Cx43266-283 treatment in the LLC-CSC-derived brain metastasis model. TAT-Cx43266-283 also induced apoptosis of tumoral cells and disrupted the cytoskeleton and vascularization of the tumor tissue in this preclinical lung cancer brain metastasis model. Conclusions: Our results suggest that TAT-Cx43266-283 is a promising antitumoral drug for lung cancer brain metastasis treatment. We identified the inhibition of ERK as an important effector, together with the inhibition of Src, in the antitumoral effect of TAT-Cx43266-283 in lung cancer brain metastasis. All this together, places TAT-Cx43266-283 one step forward into its journey to its therapeutic implementation.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Stem Cell, Cell Culture

DISEASE(S): Brain Cancer

SUBMITTER: Vinothini Rajeeve  

LAB HEAD: Pedro Rodriguez Cutillas

PROVIDER: PXD058276 | Pride | 2026-03-02

REPOSITORIES: Pride