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Resistance to the Proteasome Inhibitors: Lessons from Multiple Myeloma and Mantle Cell Lymphoma

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Proteostasis and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1233))

Abstract

Since its introduction in the clinics in early 2000s, the proteasome inhibitor bortezomib (BTZ) significantly improved the prognosis of patients with multiple myeloma (MM) and mantle cell lymphoma (MCL), two of the most challenging B cell malignancies in western countries. However, relapses following BTZ therapy are frequent, while primary resistance to this agent remains a major limitation for further development of its therapeutic potential. In the present chapter, we recapitulate the molecular mechanisms associated with intrinsic and acquired resistance to BTZ learning from MM and MCL experience, including mutations of crucial genes and activation of prosurvival signalling pathways inherent to malignant B cells. We also outline the preclinical and clinical evaluations of some potential druggable targets associated to BTZ resistance, considering the most meaningful findings of the past 10 years. Although our understanding of BTZ resistance is far from being completed, recent discoveries are contributing to develop new approaches to treat relapsed MM and MCL patients.

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Acknowledgments

MGS and MSR are part of the UbiCODE project and received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 765445. GQ is a fellow from the French Ministry of Education. MSR is also funded by the Institut National du Cancer, France (PLBIO16-251), LASSERLAB-EUROPE grant number 654148 and CONACyT-SRE (Mexico) grant 0280365.

BS acknowledges support from Ligue contre le Cancer and Fondation Française pour la Recherche contre le Myélome et les Gammapathies. GR was financially supported by Fondo de Investigación Sanitaria PI15/00102 and PI18/01383, European Regional Development Fund (ERDF) ‘Una manera de hacer Europa’.

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Authors and Affiliations

  1. ITAV-IPBS, CNRS USR3505, Toulouse, France

    Maria Gonzalez-Santamarta, Grégoire Quinet & Manuel S. Rodriguez

  2. Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona (Barcelona), Spain

    Diana Reyes-Garau & Gaël Roué

  3. Normandie University, INSERM UMR1245, UNICAEN, Caen, France

    Brigitte Sola

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  1. Maria Gonzalez-Santamarta
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  6. Manuel S. Rodriguez
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Correspondence to Manuel S. Rodriguez .

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  1. CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Spain

    Rosa Barrio

  2. CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Spain

    James D. Sutherland

  3. Centre Pierre Potier, ITAV, Toulouse Cedex 1, France

    Manuel S. Rodriguez

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Gonzalez-Santamarta, M., Quinet, G., Reyes-Garau, D., Sola, B., Roué, G., Rodriguez, M.S. (2020). Resistance to the Proteasome Inhibitors: Lessons from Multiple Myeloma and Mantle Cell Lymphoma. In: Barrio, R., Sutherland, J., Rodriguez, M. (eds) Proteostasis and Disease . Advances in Experimental Medicine and Biology, vol 1233. Springer, Cham. https://doi.org/10.1007/978-3-030-38266-7_6

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