Characterization of CDK14-18 as therapeutic targets in hepatocellular carcinoma

• Autores: Diego Martínez Alonso
• Directores de la Tesis: Marcos Malumbres (dir. tes.), Guillermo de Cárcer Díez (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2021
• Idioma: español
• Número de páginas: 113
• Tribunal Calificador de la Tesis: Francisco Xavier Real Arribas (presid.), Óscar Fernández Capetillo (secret.), David Santamaría Velilla (voc.), Amaia Lujambio Goizueta (voc.), María José Lallena Jimeno (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias médicas
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Multifold molecular events allow proliferating cells adapt to environmental signals and ensure fidelity in DNA replication and chromosome segregation. Cyclindependent kinases (CDKs) are cell cycle master regulators, integrating a complex signaling network to drive cell division and modulate transcription. These protein kinases are activated by a separate subunit named cyclin, which provides domains essential for enzymatic activity. Connected to their central implications in cell division, alterations in cyclins and CDKs are frequently associated to human disease, and particularly to cancer. Despite CDK4,6 pharmacological inhibition represents a major breakthrough in oncology, scientific and medical community aim to overcome resistance to available treatments, and to accelerate drug discovery to increase the number of treatable tumor types. In this context, delineation of the implication in human cancer of alternative CDK family members that remain uncharacterized could help uncover novel therapeutic opportunities.

    CDK14-18 are classified as cell cycle-related CDKs and belong to CDK5 subfamily. They present structural, biochemical, and functional singularities, which hindered clarification of their roles. Similar to CDK5, their expression is mainly restricted to well-differentiated post-mitotic cells, suggesting they may be dispensable for the viability of most mammalian cell types.

    Alterations in CDK14-18 expression and activity correlate with poor prognosis in tumors from different origin. Their implications in molecular pathways related to metastasis and sustained cancer progression (e.g., WNT signaling), suggest a spectrum of patients could benefit from CDK14-18 inhibition. However, the specific tumor types in which their inhibition could improve patient outcome, and the precise mechanisms underlying an eventual good clinical response, await experimental demonstration.

    In the present work, we sought to identify susceptibilities to CDK14-18 depletion in human cancer. We demonstrate how ablation of these genes induces DNA damage reducing hepatocellular carcinoma (HCC) cell proliferation, an effect significantly improved with certain combinations due to functional redundancy between these kinases. Moreover, our results highlight a cooperative effect between CDK16 implications in WNT signaling and CDK18 roles in DNA repair, as alterations in either arm hinder replication stress control. Preliminary data of CDK14-18 inhibition in murine liver tumors evidences a promising therapeutic effect, whereas genetic ablation of these genes did not lead to major physiological abnormalities, suggesting minor toxicity could be expected to associate to their inhibition in human patients