Role of the PP2A-B56Alpha heterocomplex as a specific target in acute myeloid leukemia

• Autores: Silvia Romero
• Directores de la Tesis: Goutham Narla (dir. tes.), María Dolores Odero de Dios (dir. tes.)
• Lectura: En la Universidad de Navarra ( España ) en 2024
• Idioma: inglés
• Tribunal Calificador de la Tesis: José Ángel Martínez Climent (presid.), Teresa Ezponda Itoiz (secret.), María L. Cayuela Fuentes (voc.), Vicente Cervera (voc.), Annie M O'Connor (voc.)
• Programa de doctorado: Programa de Doctorado en Medicina Aplicada y Biomedicina por la Universidad de Navarra
• Calificación: Sobresaliente Cum Laude
• Materias:
  • Ciencias médicas
    • Ciencias clínicas
      • Oncología
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• Resumen

  • Venetoclax combined with hypomethylating agents (azacitidine or decitabine) has changed the landscape for intensive chemotherapy-ineligible patients with newly diagnosed acute myeloid leukemia (AML), and venetoclax combined with azacitidine (Ven-Aza) has become the standard of care for this population. Nevertheless, primary resistance to Ven-Aza represents approximately one-third of treated AML patients, and 52% patients of those who achieved complete remission subsequently had progressive disease or morphologic relapse. Thus, a better understanding of the mechanisms of resistance to this therapy is crucial to develop new venetoclax-based combinations to improve responses in these AML patients, who otherwise have few treatment options. We have recently reported that activation of the tumor suppressor PP2A synergistically enhances the response to venetoclax in AML preclinical models, and that the observed therapeutic synergy relies on PP2A complexes containing the B56α regulatory subunit. We therefore hypothesized that a triple therapy consisting in PP2A activators, venetoclax, and azacitidine might be more effective than the clinically approved Ven-Aza combination, and that the B56α regulatory subunit might play a role in treatment response, providing a novel therapeutic approach for Ven-Aza-resistant AML. Here, we show that the addition of PP2A activators to Ven-Aza results in a synergistic enhancement of antileukemic activity in Ven-Aza-sensitive and -resistant AML cell lines, in primary cells, and in vivo models. By leveraging unbiased multi-omics-based approaches and then, validating our observations using both genetic and pharmacological tools, we demonstrate that the PP2A-B56α heterocomplex has a relevant impact on the response to this clinically approved Ven-Aza therapy, and that it is directly involved in the regulation of oxidative phosphorylation (OXPHOS) in AML, one of the main mechanisms driving treatment resistance in this disease. To our knowledge, this is the first time that PP2A-B56α has been reported to regulate OXPHOS in AML. Furthermore, our in vitro results show that PP2A-B56α, and hence OXPHOS, can be pharmacologically targeted with RPT04402, a promising novel PP2A modulator, in de novo and resistant AML. Of note, RPT04402 combined with venetoclax and azacitidine disrupts OXPHOS in treatment-resistant cells and enhances therapeutic response in vitro and in vivo. Taken together, these encouraging preclinical results provide the rationale for the clinical development of a novel targeted therapy approach based on PP2A-B56α stabilization, venetoclax, and azacitidine to counteract OXPHOS-related treatment resistance in AML.