[en] The use of targeted therapies and the early detection campaigns have improved the treatment and management of breast cancer patients in the last 10 years, increasing the survival and quality of life of these patients. Among the targeted therapies, CDK4/6 inhibitors have revolutionized the treatment of ER+/HER2- metastatic breast cancer by inducing a stable cell cycle arrest of tumour cells (cell senescence). In addition, it has recently been demonstrated that these inhibitors also promote the anti-tumour activity by the immune system and promote the elimination of tumour cells favouring tissue regeneration. On the other hand, Cx43 channels are part of the immune synapse and are involved in antigen presentation processes promoting an efficient anti-tumour immune response. Despite these results, the mechanism and signaling pathways involved in the "cleaning" of senescent tumour cells by the immune system are not yet known in detail. For this reason, in this project we propose to identify new markers and study the effect of new compounds involved in activating the anti-tumour immunity under Palbociclib treatment and mediated by Cx43. The aim of this proposal is to develop new combined therapies to promote the elimination of senescent cells and to promote tissue regeneration. The results of this project will also improve these inhibitors' efficacy and will expand the activity of CDK4/6 inhibitors to other tumour types. The identification of senolytic compounds will allow to the development of new therapeutic strategies in order to avoid drug resistance.

[gl] O uso de terapias dirixidas xunto co as campañas de detección precoz melloraron o tratamento e manexo do cancro de mama nos últimos 10 anos aumentando a supervivencia e calidade de vida das doentes. Entre as terapias dirixidas, atopamos a os inhibidores CDK4/6 que supuxeron unha revolución no tratamento do cancro de mama metastático subtipo ER+/ HER2- ao inducir un arresto estable da proliferación nas células tumorais (senescencia celular). Ademáis, descubriuse recentemente que estes inhibores actúan tamén sobre o sistema immune favorecendo a eliminación das células tumorais e promovendo a rexeneración tisular, abrindo novas xanelas para mellorar a resposta inmune anti-tumoral. Ademáis, as canles de Cx43 forman parte da sinapse das células immunes e están implicados na presentación de antígenos promovendo unha resposta immune anti-tumoral eficiente. A pesar destes resultados, hoxe en día aínda non se coñece en detalle o mecanismo e as vias de sinalización implicadas na "limpeza" das células tumorais senescentes por parte do sistema immune. Por este motivo, neste proxecto propoñemos identificar novos marcadores e estudar novos compostos que participan na activación da resposta immune en células tumorais tratadas co inhibidor Palbociclib e mediadas por la Cx43, co obxectivo de desenvolver novas terapias combinadas que favorezan a eliminación das células senescentes e promovan a rexeneración tisular. Os resultados deste proxecto van permitir aumentar a eficacia destos inhibidores e expandir a actividade dos inhibidores CDK4/6 a outros tipos tumorais. A identificación de compostos senolíticos permitirá o desenvolvemento de novas estratexias terapéuticas para evitar a resistencia a o tratamento.