Triple negative breast cancer kinome-taxonomy, prognostic and therapeutics: Role of polynucleotide kinase-phosphatase

• Autores: Sara Fernández Gaitero
• Directores de la Tesis: Miguel Angel Quintela Fandiño (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2021
• Idioma: inglés
• Número de páginas: 126
• Títulos paralelos:
  • Taxonomia del quinoma, prognostico y terapia en cáncer de mama triple negativo: Rol de la polinucleotido kinasa-fosfatasa.
• Tribunal Calificador de la Tesis: Felipe Cortés Ledesma (presid.), Ramón Colomer Bosch (secret.), Luis Manuel Manso Sanchez (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias médicas
    • Patología
      • Oncología
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and lacks prognostic and predictive markers. By Using high-throughput phosphoproteomics, the group found a set of six hyperactivated kinases that drives the phosphoprofiles of relapsing TNBC cases. We proved that this kinase-based classification of TNBC patients provides more information about the clinical outcome of patients than a classification based on their mutational profiles. In addition, drug regimens designed based on these 6 kinases show anti-tumor activity both in vitro and in in vivo models, opening the opportunity of personalized medicine by using the kinase status.

    Among the hyperactivated kinases previously identified by the group, polynucleotide kinase-phosphatase (PNKP), a DNA-damage repair protein of NHEJ pathway, was associated with the highest hazard ratio of distant metastatic relapse (Hazard ratio:2.95, P < 0.005) in early TNBC patients. This suggests that PNKP could be a target for therapy in TNBC (the most genomically unstable subgroup of breast cancer). The dependence on PNKP for DNA repair after carboplatin treatment in TNBC patients and the identification of a common mutated gene, POLQ, in TNBC cell lines sensitive to cisplatin after PNKP inhibition, suggest a possible dependence between PNKP and POLQ for DNA damage repair in TNBC patients. Depletion of PNKP and POLQ by CRISPR-Cas9 technology in MDA-MB-231 cell line conferred high sensitivity to DNA damage, with >90% reduction (p<0.001) of relative plating efficiency, suggesting that PNKP and POLQ could be potential synthetic lethal partners enhancing the response to DNA damage agents. Moreover, the interrogation of Pol θ levels in the subgroup of TNBC patients treated with carboplatin showed that combined expression of low levels of PNKP and Polθ increases the pathologic complete response rate. Sixty-two percent of TNBC patients achieved pathologic complete response compared with those that had low Polθ and high PNKP, 14.3% of whom achieved pathologic complete response (P=0.048).

    Taken together, these data suggest a possible dependence between NHEJ pathway and MMEJ pathway, where the inhibition of PNKP in TNBC patients with deficient Polθ expression could induce synthetic lethality and sensitize cancer cells to DNA damage agents