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Cited by 9Multiple Myeloma Research and TreatmentsPI3K/AKT/mTOR signaling in cancerChronic Lymphocytic Leukemia Research

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

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Sun, Kaiyan, Jin, Ling, Karolová, Jana, Vorwerk, Jan, Hailfinger, Stephan, Opalka, Bertram, Zapukhlyak, Myroslav, Lenz, Georg, Khandanpour, Cyrus·2023·Cancers
DOI 10.3390/cancers15082373PMC PMC10136620
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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.

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Crossref · 10.3390/cancers15082373

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  • Simultaneous inhibition of both PI3K and MAPK pathways is more effective in suppressing cancer growth and viability compared to targeting each pathway individually.

    “Simultaneous inhibition of both the PI3K and MAPK pathways has been shown to be more effective in suppressing cancer growth and viability compared to targeting each pathway individually [68, 83].”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [68]

    Results §3.4 reports that combining the mTOR inhibitor temsirolimus with the MEK inhibitor trametinib was synergistic for cell viability in three multiple-myeloma cell lines, but additive or ineffective in the others tested. The paper tested mTOR inhibition, not simultaneous inhibition of PI3K itself and MAPK, and its cell-line findings do not establish the stated effect on cancer growth generally. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Temsirolimus combined with the MEK inhibitor trametinib demonstrated increased anti-tumor activity, suggesting a potential synergistic effect between mTOR and MEK inhibition in MM treatment.

    “Furthermore, the efficacy of temsirolimus, when combined with the MEK inhibitor trametinib, was found to be enhanced. This combination therapy demonstrated increased anti-tumor activity, suggesting a potential synergistic effect between mTOR and MEK inhibition in MM treatment [68].”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [68]

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Cited by

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Metadata

Authors
Sun, K., Jin, L., Karolová, J., Vorwerk, J., Hailfinger, S., Opalka, B., Zapukhlyak, M., Lenz, G., & Khandanpour, C.
Affiliations
  • University Hospital Münster (DE)
  • Charles University (CZ)
  • Essen University Hospital (DE)
Corresponding author
  • Lenz, Georg
  • Khandanpour, Cyrus
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2023-04-19
Volume
15
Issue
8
Pages
2373
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers15082373
PMC
PMC10136620
OpenAlex
W4366598210
Cited by
9
References
3
Citations by year
2026: 1 · 2025: 3 · 2024: 4 · 2023: 1
FWCI
1.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • José Carreras Leukämie Stiftung (DJCLS 17R/2018, 70112392, KH331/2-3, Kha2/002/20)
  • Deutsche Krebshilfe (DJCLS 17R/2018, 70112392, KH331/2-3, Kha2/002/20)
  • Deutsche Forschungsgemeinschaft (DJCLS 17R/2018, 70112392, KH331/2-3, Kha2/002/20)
  • Faculty of Medicine at University Hospital Münster (DJCLS 17R/2018, 70112392, KH331/2-3, Kha2/002/20)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
Keywords
multiple myeloma, mTOR inhibition, MEK inhibition, temsirolimus, trametinib, combination therapy, PI3K/Akt signaling, MAPK signaling, drug synergy, G0/G1 cell cycle arrest, myeloma cell lines, drug resistance

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