Combination Treatment Targeting mTOR and MAPK Pathways Has Synergistic Activity in Multiple Myeloma
Kaiyan Sun1, Ling Jin1, Jana Karolová1,2
1Department of Medicine A, Hematology, Hemostaseology, Oncology and Pneumology, University Hospital Münster, 48149 Münster, Germany.
Cancers
|May 16, 2023
Summary
The mTOR inhibitor temsirolimus halts multiple myeloma cell growth. Combining temsirolimus with the MEK inhibitor trametinib enhances this effect, offering a new therapeutic strategy for this incurable cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple myeloma (MM) is an incurable B cell malignancy with frequent relapses.
- The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is crucial for cell survival and proliferation and is activated in MM.
- Novel therapeutic strategies are needed due to the poor prognosis and resistance to existing treatments.
Purpose of the Study:
- To evaluate the efficacy of PI3K and mTOR inhibitors in multiple myeloma cell lines.
- To investigate the potential of combining mTOR and Mitogen-activated protein kinase kinase (MEK) inhibition for MM treatment.
Main Methods:
- Testing PI3K and mTOR inhibitors on MM cell lines representing different prognostic subtypes.
- Assessing the impact of temsirolimus (mTOR inhibitor) on PI3K pathway signaling.
- Evaluating the synergistic effect of combining temsirolimus with trametinib (MEK inhibitor).
Main Results:
- MM cell lines showed resistance to PI3K inhibition.
- Temsirolimus treatment reduced proliferation by inducing G0/G1 cell cycle arrest and decreasing PI3K pathway phosphorylation.
- Combining temsirolimus with trametinib significantly amplified the anti-myeloma effect.
Conclusions:
- mTOR inhibition, but not PI3K inhibition alone, effectively reduces MM cell proliferation.
- Simultaneous inhibition of mTOR and MEK presents a promising novel therapeutic strategy for multiple myeloma.
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