2024-03-28T21:14:29Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1688962020-12-13T09:14:35Zcom_10261_112com_10261_1col_10261_365
Paíno, Teresa
García-Gómez, Antonio
González-Méndez, Lorena
San-Segundo, Laura
Hernández-García, Susana
López-Iglesias, Ana-Alicia
Algarín, Esperanza M.
Martín-Sánchez, Montserrat
Corbacho-González, David
Ortiz-de-Solorzano, Carlos
Corchete, Luis A.
Gutiérrez, Norma Carmen
Mateos, Maria Victoria
Garayoa, Mercedes
Ocio, Enrique M.
2018-08-20T10:31:42Z
2018-08-20T10:31:42Z
2017
Clinical Cancer Research 23(1): 225-238 (2017)
http://hdl.handle.net/10261/168896
10.1158/1078-0432.CCR-16-0230
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100014180
27440267
[Purpose]: PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models. [Experimental Design]: In vitro/ex vivo cytotoxicity of PIM447 was evaluated on myeloma cell lines and patient samples. Synergistic combinations with standard treatments were analyzed with Calcusyn Software. PIM447 effects on bone cells were assessed on osteogenic and osteoclastogenic cultures. The mechanisms of PIM447 were explored by immunoblotting, qPCR, and immunofluorescence. A murine model of disseminated multiple myeloma was employed for in vivo studies. [Results]: PIM447 is cytotoxic for myeloma cells due to cell-cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of mTORC1 pathway. Importantly, PIM447 demonstrates a very strong synergy with different standard treatments such as bortezomib + dexamethasone (combination index, CI = 0.002), lenalidomide + dexamethasone (CI = 0.065), and pomalidomide + dexamethasone (CI = 0.077). PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes, and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization. Finally, PIM447 significantly reduced the tumor burden and prevented tumor-associated bone loss in a disseminated murine model of human myeloma. [Conclusions]: Our results demonstrate dual antitumoral and bone-protective effects of PIM447. This fact, together with the very strong synergy exhibited with standard-of-care treatments, supports the future clinical development of this drug in multiple myeloma.
eng
openAccess
Bone disease
Drug combinations
Multiple myeloma
Treatment
pan-PIM inhibitor
The novel pan-PIM kinase inhibitor, PIM447, displays dual antimyeloma and bone-protective effects, and potently synergizes with current standards of care
artículo