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

Kaiyan Sun, Ling Jin, Jana Karolová, Jan Vorwerk, Stephan Hailfinger, Bertram Opalka, Myroslav Zapukhlyak, Georg Lenz*, Cyrus Khandanpour*

*Korrespondierende/r Autor/-in für diese Arbeit

Abstract

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 G0/G1 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.

OriginalspracheEnglisch
Aufsatznummer2373
ZeitschriftCancers
Jahrgang15
Ausgabenummer8
ISSN2072-6694
DOIs
PublikationsstatusVeröffentlicht - 04.2023

Strategische Forschungsbereiche und Zentren

  • Profilbereich: Lübeck Integrated Oncology Network (LION)
  • Zentren: Universitäres Cancer Center Schleswig-Holstein (UCCSH)

DFG-Fachsystematik

  • 205-14 Hämatologie, Onkologie

Zitieren