Estamos realizando la búsqueda. Por favor, espere...

 Detalle_Publicacion

Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma

Abstract: Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. Results: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. Conclusions: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.

 Fuente: Cancers (Basel) . 2020 Sep 24;12(10):2743

Editorial: MDPI

 Año de publicación: 2020

Nº de páginas: 20

Tipo de publicación: Artículo de Revista

 DOI: 10.3390/cancers12102743

ISSN: 2072-6694

Url de la publicación: https://doi.org/10.3390/cancers12102743

Autores/as

PAÍNO, TERESA

GONZÁLEZ MÉNDEZ, LORENA

SAN SEGUNDO, LAURA

CORCHETE, LUIS A.

HERNÁNDEZ GARCÍA, SUSANA

DÍAZ TEJEDOR, ANDREA

ALGARÍN, ESPERANZA M.

MOGOLLÓN, PEDRO

MARTÍN SÁNCHEZ, MONTSERRAT

GUTIÉRREZ, NORMA C.

MATEOS, MARÍA VICTORIA

GARAYOA, MERCEDES