Circulating biosignatures in multiple myeloma and their role in multidrug resistance

Abstract

A major obstacle to chemotherapeutic success in cancer treatment is the development of drug resistance. This occurs when a tumour fails to reduce in size after treatment or when there is clinical relapse after an initial positive response to treatment. A unique and serious type of resistance is multidrug resistance (MDR). MDR causes the simultaneous cross resistance to unrelated drugs used in chemotherapy. MDR can be acquired through genetic alterations following drug exposure, or as discovered by us, through alternative pathways mediated by the transfer of functional MDR proteins and nucleic acids by extracellular vesicles (M Bebawy V Combes E Lee R Jaiswal J Gong A Bonhoure GE Grau, 23 9 1643 1649, 2009).Multiple myeloma is an incurable cancer of bone marrow plasma cells. Treatment involves high dose combination chemotherapy and patient response is unpredictable and variable due to the presence of multisite clonal tumour infiltrates. This clonal heterogeneity can contribute to the development of MDR. There is currently no approved clinical test for the minimally invasive testing of MDR in myeloma.Extracellular vesicles comprise a group of heterogeneous cell-derived membranous structures which include; exosomes, microparticles (microvesicles), migrasomes and apoptotic bodies. Extracellular vesicles serve an important role in cellular communication through the intercellular transfer of cellular protein, nucleic acid and lipid cargo. Of these, microparticles (MPs) originate from the cell plasma membrane and vary in size from 0.1-1um. We have previously shown that MPs confer MDR through the transfer of resistance proteins and nucleic acids. A test for the early detection of MDR would benefit clinical decision making, improve survival and support rational drug use. This review focuses on microparticles as novel clinical biomarkers for the detection of MDR in Myeloma and discusses their role in the therapeutic management of the disease.

Exosome inhibition improves response to first‐line therapy in small cell lung cancer

“…The functional proteins or non‐coding RNAs contained in exosomes secreted by tumour cells mediate drug resistance through the regulation of drug efflux and metabolism 29 . Research suggests that the diversion of EVs from cancer cells contributes to their resistance to chemotherapeutic agents through increased active drug efflux 22,28–46 . Recent pharmacological studies have shown that inhibiting EV release could be a new strategy to make cancer cells more susceptible to anticancer drug treatment 32,37–39 .…”

“… 29 Research suggests that the diversion of EVs from cancer cells contributes to their resistance to chemotherapeutic agents through increased active drug efflux. 22 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 Recent pharmacological studies have shown that inhibiting EV release could be a new strategy to make cancer cells more susceptible to anticancer drug treatment. 32 , 37 , 38 , 39 While significant progress has been made in exosome/sEV research in recent years, no medications that specifically target the inhibition of sEV secretion have been approved for human use.…”

Pathways to therapy resistance: The sheltering effect of the bone marrow microenvironment to multiple myeloma cells

“…These vesicles function as transporters of bioactive molecules, such as proteins, lipids, and nucleic acids, enabling communication between cells and impacting the behavior of the cells they interact with. Exosomes derived from BMSCs and myeloma cells are of great significance in the study of MM [ 143 ]. They possess a wide range of signaling molecules, including cytokines, growth factors, and miRNAs, that have the ability to modify the characteristics of myeloma cells and bolster their ability to survive and resist treatment [ 143 ].…”

“…Exosomes derived from BMSCs and myeloma cells are of great significance in the study of MM [ 143 ]. They possess a wide range of signaling molecules, including cytokines, growth factors, and miRNAs, that have the ability to modify the characteristics of myeloma cells and bolster their ability to survive and resist treatment [ 143 ].…”

“…In addition, exosomes derived from myeloma cells that are resistant to drugs have the ability to transfer traits of resistance to cells that are sensitive to drugs, thereby facilitating the spread of resistance among the population of tumor cells [ 143 ]. The transfer of resistance mechanisms occurs horizontally by transporting drug-resistant proteins like ABC transporters or miRNAs that target drug sensitivity pathways [ 143 ]. Due to this, myeloma cells that were once sensitive become resistant, which makes treatment strategies more complex and contributes to the recurrence of the disease.…”