Journal Article Epublish
PubMed: 42742967 DOI: 10.1172/jci.insight.205218
Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML.
JCI Insight 11(20)
Authors: Silvia Romero-Murillo, Irene Peris, Anna Maria Lucianò, Nerea Marcotegui, Carmen Vicente, Brian Tran, Kelsey Barrie, Caitlin M O'Connor, Andrea Torres-López, Maria C Mateos, Maria L Cayuela, Victoriano Mulero, Joaquín Fernández-Irigoyen, Enrique Santamaría, Maria D Odero, Goutham Narla
Affiliations
- Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Navarra, Spain.
- Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
- Centro de Investigación Médica Aplicada and.
- Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
- Department of Internal Medicine, Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, Michigan, USA. Roger Cancer Center, The University of Michigan Health, Ann Arbor, Michigan, USA.
- Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain. Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Murcia, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
- Department of Pharmacology, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
- Department of Internal Medicine, Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
- Roger Cancer Center, The University of Michigan Health, Ann Arbor, Michigan, USA.
- Hematology Service, HUN, Pamplona, Spain.
- Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain. Hematology Service, HUN, Pamplona, Spain.
- Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and IMIB, Murcia, Spain.
- Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain.
- Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Murcia, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
- Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain. Centro de Investigación Médica Aplicada and. Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
- Department of Cancer Biology, The University of Michigan, Ann Arbor, Michigan, USA.
Abstract
Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in patients with acute myeloid leukemia (AML). Drug-resistant cells exhibit an enhanced reliance on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need. We recently demonstrated that the specific activation of the phosphatase PP2A-B56α enhances the proapoptotic efficacy of venetoclax in AML. Here, through leveraging unbiased multi-omics-based approaches and using both genetic and pharmacological tools, we define key roles for the tumor suppressor PP2A-B56α complex in OXPHOS regulation and treatment response in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56α heterocomplex with the potentially novel PP2A molecular glue activator, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza-sensitive and -resistant AML cell lines, primary cells, and in vivo models. Together, our work supports further research on targeted combination therapy approaches based on PP2A-B56α stabilization to counteract OXPHOS-related treatment resistance and improve AML responses in a patient population with historically poor outcomes.
MeSH
Cells, Biomedical Research, Azacitidine, Therapeutics