Combination Treatment Targeting mTOR and MAPK Pathways Has Synergistic Activity in Multiple Myeloma.

Autor:	Sun K; Department of Medicine A, Hematology, Hemostaseology, Oncology and Pneumology, University Hospital Münster, 48149 Münster, Germany., Jin L; Department of Medicine A, Hematology, Hemostaseology, Oncology and Pneumology, University Hospital Münster, 48149 Münster, Germany., Karolová J; Department of Medicine A, Hematology, Hemostaseology, Oncology and Pneumology, University Hospital Münster, 48149 Münster, Germany.; Institute of Pathological Physiology, First Faculty of Medicine, Charles University, 12108 Prague, Czech Republic., Vorwerk J; Department of Medicine A, Hematology, Hemostaseology, Oncology and Pneumology, University Hospital Münster, 48149 Münster, Germany., Hailfinger S; Department of Medicine A, Hematology, Hemostaseology, Oncology and Pneumology, University Hospital Münster, 48149 Münster, Germany., Opalka B; Department of Hematology and Stem Cell Transplantation, West German Cancer Center (WTZ), University Hospital Essen, 45147 Essen, Germany., Zapukhlyak M; Department of Medicine A, Hematology, Hemostaseology, Oncology and Pneumology, University Hospital Münster, 48149 Münster, Germany., Lenz G; Department of Medicine A, Hematology, Hemostaseology, Oncology and Pneumology, University Hospital Münster, 48149 Münster, Germany., Khandanpour C; Department of Medicine A, Hematology, Hemostaseology, Oncology and Pneumology, University Hospital Münster, 48149 Münster, Germany.; Department of Hematology and Oncology, University Hospital Schleswig-Holstein and University of Lübeck, 23538 Lübeck, Germany.
Jazyk:	angličtina
Zdroj:	Cancers [Cancers (Basel)] 2023 Apr 19; Vol. 15 (8). Date of Electronic Publication: 2023 Apr 19.
DOI:	10.3390/cancers15082373
Abstrakt:	Multiple myeloma (MM) is an incurable, malignant B cell disorder characterized by frequent relapses and a poor prognosis. Thus, new therapeutic approaches are warranted. The phosphatidylinositol-3-kinase (PI3K) pathway plays a key role in many critical cellular processes, including cell proliferation and survival. Activated PI3K/AKT (protein kinases B)/mTOR (mammalian target of rapamycin) signaling has been identified in MM primary patient samples and cell lines. In this study, the efficacy of PI3K and mTOR inhibitors in various MM cell lines representing three different prognostic subtypes was tested. Whereas MM cell lines were rather resistant to PI3K inhibition, treatment with the mTOR inhibitor temsirolimus decreases the phosphorylation of key molecules in the PI3K pathway in MM cell lines, leading to G 0 /G 1 cell cycle arrest and thus reduced proliferation. Strikingly, the efficacy of temsirolimus was amplified by combining the treatment with the Mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Our findings provide a scientific rationale for the simultaneous inhibition of mTOR and MEK as a novel strategy for the treatment of MM.
Databáze:	MEDLINE
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