Targeting mTOR signaling pathways in multiple myeloma: biology and implication for therapy

Multiple Myeloma (MM), a cancer of terminally differentiated plasma cells, is the second most prevalent hematological malignancy and is incurable due to the inevitable development of drug resistance. Intense protein synthesis is a distinctive trait of MM cells, supporting the massive production of clonal immunoglobulins or free light chains. The mammalian target of rapamycin (mTOR) kinase is appreciated as a master regulator of vital cellular processes, including regulation of metabolism and protein synthesis, and can be found in two multiprotein complexes, mTORC1 and mTORC2. Dysregulation of these complexes is implicated in several types of cancer, including MM. Since mTOR has been shown to be aberrantly activated in a large portion of MM patients and to play a role in stimulating MM cell survival and resistance to several existing therapies, understanding the regulation and functions of the mTOR complexes is vital for the development of more effective therapeutic strategies. This review provides a general overview of the mTOR pathway, discussing key discoveries and recent insights related to the structure and regulation of mTOR complexes. Additionally, we highlight findings on the mechanisms by which mTOR is involved in protein synthesis and delve into mTOR-mediated processes occurring in MM. Finally, we summarize the progress and current challenges of drugs targeting mTOR complexes in MM.

• Publication year

  2024

• Venue

  Cell Communication and Signaling

• Publication date

  2024-06-11

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/s12964-024-01699-3PMID 38862983PMCID 11165851
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Breaking through Multiple Myeloma: A Paradigm for a Comprehensive Tumor Ecosystem Targeting

  2023cited by this paper
• S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability in multiple myeloma

  2023cited by this paper
• Metformin confers sensitisation to syrosingopine in multiple myeloma cells by metabolic blockage and inhibition of protein synthesis

  2023cited by this paper
• Immunotherapy for the treatment of multiple myeloma

  2022cited by this paper
• Targeting the β2‐adrenergic receptor increases chemosensitivity in multiple myeloma by induction of apoptosis and modulating cancer cell metabolism

  2022cited by this paper
• New mechanistic insights into the RAS-SIN1 interaction at the membrane

  2022cited by this paper
• Oncolytic Avian Reovirus p17-Modulated Inhibition of mTORC1 by Enhancement of Endogenous mTORC1 Inhibitors Binding to mTORC1 To Disrupt Its Assembly and Accumulation on Lysosomes

  2022cited by this paper
• Lenalidomide, bortezomib and dexamethasone induction therapy for the treatment of newly diagnosed multiple myeloma: a practical review

  2022cited by this paper
• mTORC1-Inhibition Potentiating Metabolic Block by Tyrosine Kinase Inhibitor Ponatinib in Multiple Myeloma

  2022cited by this paper
• Multiple myeloma: 2022 update on diagnosis, risk stratification, and management

  2022cited by this paper
• Structural insights into Ras regulation by SIN1

  2022cited by this paper
• The homeostatic regulation of ribosome biogenesis.

  2022cited by this paper
• RNA Polymerases I and III in development and disease.

  2022cited by this paper
• Turnover of the mTOR inhibitor, DEPTOR, and downstream AKT phosphorylation in multiple myeloma cells, is dependent on ERK1-mediated phosphorylation

  2022cited by this paper
• Regulation of Nucleolar Activity by MYC

  2022cited by this paper
• Pyrroline-5-Carboxylate Reductase 1: a novel target for sensitizing multiple myeloma cells to bortezomib by inhibition of PRAS40-mediated protein synthesis

  2022cited by this paper
• Diagnosis and Management of Multiple Myeloma: A Review.

  2022cited by this paper
• mTOR- and LARP1-dependent regulation of TOP mRNA poly(A) tail and ribosome loading.

  2022cited by this paper
• G9a/GLP targeting in MM promotes autophagy-associated apoptosis and boosts proteasome inhibitor-mediated cell death.

  2021cited by this paper
• mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.

  2021cited by this paper
• mTORC1 silencing during intestinal epithelial Caco-2 cell differentiation is mediated by the activation of the AMPK/TSC2 pathway.

  2021cited by this paper
• mTORC1 promotes TOP mRNA translation through site-specific phosphorylation of LARP1

  2021cited by this paper
• Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

  2021influential reference
• CART-Cell Therapy: Recent Advances and New Evidence in Multiple Myeloma

  2021cited by this paper
• Multiple Myeloma Incidence and Mortality Around the Globe; Interrelations Between Health Access and Quality, Economic Resources, and Patient Empowerment

  2020cited by this paper
• The 3.2-Å resolution structure of human mTORC2

  2020cited by this paper
• Glutamine and asparagine activate mTORC1 independently of Rag GTPases

  2020cited by this paper
• A Phase I Study of Everolimus and Bendamustine in Patients With Relapsed/Refractory Lymphoid Hematologic Malignancies.

  2020cited by this paper
• Leucine regulates autophagy via acetylation of the mTORC1 component raptor

  2020cited by this paper
• The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

  2020cited by this paper
• Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways

  2020cited by this paper
• Mouse tumor susceptibility genes identify drug combinations for multiple myeloma

  2020cited by this paper
• TGFβ acts through PDGFRβ to activate mTORC1 via the Akt/PRAS40 axis and causes glomerular mesangial cell hypertrophy and matrix protein expression

  2020cited by this paper
• The GATOR–Rag GTPase pathway inhibits mTORC1 activation by lysosome-derived amino acids

  2020cited by this paper
• Multiple myeloma current treatment algorithms

  2020influential reference
• CC-223, NSC781406, and BGT226 Exerts a Cytotoxic Effect Against Pancreatic Cancer Cells via mTOR Signaling

  2020cited by this paper
• AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation

  2020cited by this paper
• Structural insights into TSC complex assembly and GAP activity on Rheb

  2020cited by this paper
• Acetyl-CoA Derived from Hepatic Peroxisomal β-Oxidation Inhibits Autophagy and Promotes Steatosis via mTORC1 Activation.

  2020cited by this paper
• NUPR1 Silencing Induces Autophagy-Mediated Apoptosis in Multiple Myeloma Cells Through the PI3K/AKT/mTOR Pathway

  2020cited by this paper
• A cysteine near the C-terminus of UCH-L1 is dispensable for catalytic activity but is required to promote AKT phosphorylation, eIF4F assembly, and malignant B-cell survival

  2019cited by this paper
• Direct physical interaction of active Ras with mSIN1 regulates mTORC2 signaling

  2019cited by this paper
• AMPK directly activates mTORC2 to promote cell survival during acute energetic stress

  2019cited by this paper
• The mTOR Inhibitor Everolimus Overcomes CXCR4-Mediated Resistance to Histone Deacetylase Inhibitor Panobinostat through Inhibition of p21 and Mitotic Regulators.

  2019cited by this paper
• A Novel Therapeutic Induces DEPTOR Degradation in Multiple Myeloma Cells with Resulting Tumor Cytotoxicity

  2019cited by this paper
• A combination regimen of low-dose bortezomib and rapamycin prolonged the graft survival in a murine allogeneic islet transplantation model.

  2019cited by this paper
• RAPTOR promotes colorectal cancer proliferation by inducing mTORC1 and upregulating ribosome assembly factor URB1

  2019cited by this paper
• PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells

  2019cited by this paper
• NVP-BEZ235-induced autophagy as a potential therapeutic approach for multiple myeloma.

  2019cited by this paper
• Two conserved glycine residues in mammalian and Dictyostelium Rictor are required for mTORC2 activity and integrity

  2019cited by this paper
• Impaired Ribosomal Biogenesis by Noncanonical Degradation of β-Catenin during Hyperammonemia

  2019cited by this paper
• A review on tumor heterogeneity and evolution in multiple myeloma: pathological, radiological, molecular genetics, and clinical integration

  2019cited by this paper
• Metabolic, Anti-apoptotic and Immune Evasion Strategies of Primary Human Myeloma Cells Indicate Adaptations to Hypoxia*

  2019cited by this paper
• Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease

  2019cited by this paper
• Cross Talk Networks of Mammalian Target of Rapamycin Signaling With the Ubiquitin Proteasome System and Their Clinical Implications in Multiple Myeloma.

  2019cited by this paper
• mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy

  2019cited by this paper
• Functional Modules of the Proteostasis Network.

  2019cited by this paper
• Disruption of scaffolding function of mLST8 selectively inhibits mTORC2 assembly and function and suppresses mTORC2-dependent tumor growth in vivo.

  2019cited by this paper
• Combining the mammalian target of rapamycin inhibitor, rapamycin, with resveratrol has a synergistic effect in multiple myeloma

  2018cited by this paper
• Knockdown of NUPR1 inhibits the growth of U266 and RPMI8226 multiple myeloma cell lines via activating PTEN and caspase activation‑dependent apoptosis.

  2018cited by this paper
• RANKL-induced c-Src activation contributes to conventional anti-cancer drug resistance and dasatinib overcomes this resistance in RANK-expressing multiple myeloma cells

  2018cited by this paper
• Ubiquitination of Rheb governs growth factor-induced mTORC1 activation

  2018cited by this paper
• The Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response

  2018cited by this paper
• Neural Regulation of Bone and Bone Marrow.

  2018cited by this paper
• Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways

  2018cited by this paper
• Everolimus shows synergistic antimyeloma effects with bortezomib via the AKT/mTOR pathway

  2018cited by this paper
• Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma

  2018cited by this paper
• Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression.

  2018cited by this paper
• Dual inhibition of mTORC1/2 by DCZ0358 induces cytotoxicity in multiple myeloma and overcomes the protective effect of the bone marrow microenvironment.

  2018cited by this paper
• CC-223 blocks mTORC1/C2 activation and inhibits human hepatocellular carcinoma cells in vitro and in vivo

  2017cited by this paper
• Deptor: not only a mTOR inhibitor

  2017cited by this paper
• A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer

  2017cited by this paper
• AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance.

  2017cited by this paper
• Endoplasmic reticulum stress induces autophagy and apoptosis while inhibiting proliferation and drug resistance in multiple myeloma through the PI3K/Akt/mTOR signaling pathway

  2017cited by this paper
• 4.4 Å Resolution Cryo-EM structure of human mTOR Complex 1

  2016cited by this paper
• Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells

  2016cited by this paper
• Elevated Translation Initiation Factor eIF4E Is an Attractive Therapeutic Target in Multiple Myeloma

  2016cited by this paper
• TAK‐228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non‐Hodgkin lymphoma, or Waldenström's macroglobulinemia

  2016cited by this paper
• Architecture of human mTOR complex 1

  2016cited by this paper
• La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1)*

  2015cited by this paper
• Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223.

  2015cited by this paper
• PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex.

  2015cited by this paper
• A phase I dose‐escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC‐223 in patients with advanced solid tumors or multiple myeloma

  2015cited by this paper
• Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study

  2015cited by this paper
• Multiple myeloma proteostasis can be targeted via translation initiation factor eIF4E.

  2015cited by this paper
• A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation.

  2015cited by this paper
• Targeting autophagy in multiple myeloma.

  2015cited by this paper
• Control of Paip1-Eukayrotic Translation Initiation Factor 3 Interaction by Amino Acids through S6 Kinase

  2014cited by this paper
• Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma

  2014cited by this paper
• Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide

  2014cited by this paper
• Delineating the mTOR Kinase Pathway Using a Dual TORC1/2 Inhibitor, AZD8055, in Multiple Myeloma

  2014cited by this paper
• The FoxO–BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress

  2014cited by this paper
• International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.

  2014cited by this paper
• Improving Type 2 Diabetes Through a Distinct Adrenergic Signaling Pathway Involving mTORC2 That Mediates Glucose Uptake in Skeletal Muscle

  2014cited by this paper
• Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

  2013cited by this paper
• Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation.

  2013cited by this paper
• Signal integration by mTORC1 coordinates nutrient input with biosynthetic output

  2013cited by this paper
• Knockdown of DEPTOR inhibits cell proliferation and increases chemosensitivity to melphalan in human multiple myeloma RPMI-8226 cells via inhibiting PI3K/AKT activity

  2013cited by this paper
• MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells

  2013cited by this paper
• Everolimus enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro-apoptotic and cell-cycle-progression regulatory proteins.

  2013cited by this paper

• Regulation of stress tolerance by CREB1 sustains multiple myeloma cell survival

  2026cites this paper
• Targeting PRKCN, an Essential Driver Orchestrating mTOR-IRF4 Axis Independently of Kinase Activity, in Multiple Myeloma.

  2026cites this paper
• The clinically available supplement pyruvate enhances the therapeutic effect of bortezomib in MM by modulating mitochondrial metabolism.

  2026cites this paper
• The Effect of Valine on the Synthesis of α-Casein in MAC-T Cells and the Expression and Phosphorylation of Genes Related to the mTOR Signaling Pathway

  2025cites this paper
• Regulatory role of E3 ubiquitin ligases in multiple myeloma: from molecular mechanisms to therapeutic strategies

  2025cites this paper
• Proteomic Analysis of Bone Marrow CD138+ Cells to Identify Proteins Associated With the Response of Multiple Myeloma Patients to Commonly Used Therapeutic Regimens

  2025cites this paper
• Recent advances of the mechanistic target of rapamycin (mTOR) inhibitors for drug discovery.

  2025cites this paper
• Small-molecule mTOR inhibitors in the clinic: From bench to bedside.

  2025cites this paper
• Effects of omega-3 fatty acids (n-3 PUFAs) on cardiovascular and muscular health across various populations: a review of supplementation benefits

  2025cites this paper
• Non-covalent mTOR inhibition suppresses NLRP3-GSDMD inflammasome-mediated pyroptosis

  2025cites this paper
• Dysregulated mTOR signaling in Alzheimer's disease: Linking pathogenic mechanisms to emerging therapeutic strategies

  2025cites this paper
• BCMA biology and therapeutic targeting in multiple myeloma: From ligand signaling to antigen escape.

  2025cites this paper
• Syntenin inhibition impairs stroma‐tumor communication in multiple myeloma and improves bortezomib treatment efficiency

  2025cites this paper
• Two cGMP-dependent protein kinases have opposing effects on molt-inhibiting hormone regulation of Y-organ ecdysteroidogenesis.

  2025cites this paper
• Exploring the Role of Hypoxia and HIF-1α in the Intersection of Type 2 Diabetes Mellitus and Endometrial Cancer

  2025cites this paper
• Targeting the mTOR-Autophagy Axis: Unveiling Therapeutic Potentials in Osteoporosis

  2024cites this paper
• RMC-7977 a broad RAS inhibitor increases the sensitivity towards Bortezomib

  year unknowncites this paper