Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors

Overview

Journal Front Oncol

Specialty Oncology

Date 2022 Jun 13

PMID 35692781

Authors

Jonas Schwestermann

Andrej Besse

Christoph Driessen

Lenka Besse

Affiliations

Soon will be listed here.

Abstract

Virtually all patients with multiple myeloma become unresponsive to treatment with proteasome inhibitors over time. Relapsed/refractory multiple myeloma is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations, diverse proteomic and metabolic alterations, and profound changes of the bone marrow microenvironment. However, the molecular mechanisms that drive resistance to proteasome inhibitors within the context of the bone marrow microenvironment remain elusive. In this review article, we summarize the latest knowledge about the complex interaction of malignant plasma cells with its surrounding microenvironment. We discuss the pivotal role of metabolic reprograming of malignant plasma cells within the tumor microenvironment with a subsequent focus on metabolic rewiring in plasma cells upon treatment with proteasome inhibitors, driving multiple ways of adaptation to the treatment. At the same time, mutual interaction of plasma cells with the surrounding tumor microenvironment drives multiple metabolic alterations in the bone marrow. This provides a tumor-promoting environment, but at the same time may offer novel therapeutic options for the treatment of relapsed/refractory myeloma patients.

Citing Articles

Multilevel Mechanisms of Cancer Drug Resistance.

Roszkowska M Int J Mol Sci. 2024; 25(22).

PMID: 39596466 PMC: 11594576. DOI: 10.3390/ijms252212402.

Different evasion strategies in multiple myeloma.

Wang C, Wang W, Wang M, Deng J, Sun C, Hu Y Front Immunol. 2024; 15:1346211.

PMID: 38464531 PMC: 10920326. DOI: 10.3389/fimmu.2024.1346211.

Ixazomib-Thalidomide-Dexamethasone Induction Followed by Ixazomib or Placebo Maintenance in Nontransplant Eligible Newly Diagnosed Multiple Myeloma Patients: Long-term Results of HOVON-126/NMSG 21.13.

Groen K, Schjesvold F, van der Holt B, Levin M, Seefat M, Hansson M Hemasphere. 2023; 7(9):e940.

PMID: 37663673 PMC: 10470677. DOI: 10.1097/HS9.0000000000000940.

Shutting off the fuel supply to target metabolic vulnerabilities in multiple myeloma.

Rana P, Goparaju K, Driscoll J Front Oncol. 2023; 13:1141851.

PMID: 37361580 PMC: 10285382. DOI: 10.3389/fonc.2023.1141851.

An Integrated Methodology to Quantify the Glycolytic Stress in Plasma Cell Myeloma in Response to Cytotoxic Drugs.

Lepore A, Kaci F, Bubici C, Papa S Methods Mol Biol. 2023; 2675:285-296.

PMID: 37258771 DOI: 10.1007/978-1-0716-3247-5_21.

References

Parzych K, Saavedra-Garcia P, Valbuena G, Al-Sadah H, Robinson M, Penfold L . The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation. Oncogene. 2019; 38(17):3216-3231. PMC: 6756015. DOI: 10.1038/s41388-018-0651-z. View

Ray A, Das D, Song Y, Richardson P, Munshi N, Chauhan D . Targeting PD1-PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia. 2015; 29(6):1441-4. PMC: 5703039. DOI: 10.1038/leu.2015.11. View

Yu W, Cao D, Li Q, Mei H, Hu Y, Guo T . Adipocytes secreted leptin is a pro-tumor factor for survival of multiple myeloma under chemotherapy. Oncotarget. 2016; 7(52):86075-86086. PMC: 5349898. DOI: 10.18632/oncotarget.13342. View

Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M . Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007; 109(9):3812-9. DOI: 10.1182/blood-2006-07-035972. View

Driessen C, Kraus M, Joerger M, Rosing H, Bader J, Hitz F . Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08). Haematologica. 2015; 101(3):346-55. PMC: 4815726. DOI: 10.3324/haematol.2015.135780. View

Riz I, Hawley T, Hawley R . KLF4-SQSTM1/p62-associated prosurvival autophagy contributes to carfilzomib resistance in multiple myeloma models. Oncotarget. 2015; 6(17):14814-31. PMC: 4558117. DOI: 10.18632/oncotarget.4530. View

Gao Q, Wang L, Wang S, Huang B, Jing Y, Su J . Bone Marrow Mesenchymal Stromal Cells: Identification, Classification, and Differentiation. Front Cell Dev Biol. 2022; 9:787118. PMC: 8762234. DOI: 10.3389/fcell.2021.787118. View

Frassanito M, De Veirman K, Desantis V, Di Marzo L, Vergara D, Ruggieri S . Halting pro-survival autophagy by TGFβ inhibition in bone marrow fibroblasts overcomes bortezomib resistance in multiple myeloma patients. Leukemia. 2015; 30(3):640-8. DOI: 10.1038/leu.2015.289. View

Chang C, Qiu J, OSullivan D, Buck M, Noguchi T, Curtis J . Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015; 162(6):1229-41. PMC: 4864363. DOI: 10.1016/j.cell.2015.08.016. View

10.

Castella B, Foglietta M, Sciancalepore P, Rigoni M, Coscia M, Griggio V . Anergic bone marrow Vγ9Vδ2 T cells as early and long-lasting markers of PD-1-targetable microenvironment-induced immune suppression in human myeloma. Oncoimmunology. 2015; 4(11):e1047580. PMC: 4589055. DOI: 10.1080/2162402X.2015.1047580. View

11.

Wegiel B, Vuerich M, Daneshmandi S, Seth P . Metabolic Switch in the Tumor Microenvironment Determines Immune Responses to Anti-cancer Therapy. Front Oncol. 2018; 8:284. PMC: 6099109. DOI: 10.3389/fonc.2018.00284. View

12.

Shen C, Yuan Z, Liu Y, Hu G . Increased numbers of T helper 17 cells and the correlation with clinicopathological characteristics in multiple myeloma. J Int Med Res. 2012; 40(2):556-64. DOI: 10.1177/147323001204000217. View

13.

Schreiber R, Old L, Smyth M . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331(6024):1565-70. DOI: 10.1126/science.1203486. View

14.

Besse L, Besse A, Mendez-Lopez M, Vasickova K, Sedlackova M, Vanhara P . A metabolic switch in proteasome inhibitor-resistant multiple myeloma ensures higher mitochondrial metabolism, protein folding and sphingomyelin synthesis. Haematologica. 2019; 104(9):e415-e419. PMC: 6717569. DOI: 10.3324/haematol.2018.207704. View

15.

Effenberger M, Bommert K, Kunz V, Kruk J, Leich E, Rudelius M . Glutaminase inhibition in multiple myeloma induces apoptosis MYC degradation. Oncotarget. 2017; 8(49):85858-85867. PMC: 5689652. DOI: 10.18632/oncotarget.20691. View

16.

Boyle W, Simonet W, Lacey D . Osteoclast differentiation and activation. Nature. 2003; 423(6937):337-42. DOI: 10.1038/nature01658. View

17.

Chng W, Huang G, Chung T, Ng S, Gonzalez-Paz N, Troska-Price T . Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. Leukemia. 2011; 25(6):1026-35. PMC: 3432644. DOI: 10.1038/leu.2011.53. View

18.

Acosta-Alvear D, Cho M, Wild T, Buchholz T, Lerner A, Simakova O . Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits. Elife. 2015; 4:e08153. PMC: 4602331. DOI: 10.7554/eLife.08153. View

19.

Ehrlich L, Chung H, Ghobrial I, Choi S, Morandi F, Colla S . IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood. 2005; 106(4):1407-14. DOI: 10.1182/blood-2005-03-1080. View

20.

Pallardo F, Markovic J, Garcia J, Vina J . Role of nuclear glutathione as a key regulator of cell proliferation. Mol Aspects Med. 2009; 30(1-2):77-85. DOI: 10.1016/j.mam.2009.01.001. View