IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies

Elisa Bergaggio, Chiara Riganti, Giulia Garaffo, Nicoletta Vitale, Elisabetta Mereu, Cecilia Bandini, Elisa Pellegrino, Verdiana Pullano, Paola Omedè, Katia Todoerti, Luciano Cascione, Valentina Audrito, Anna Riccio, Antonio Rossi, Francesco Bertoni, Silvia Deaglio, Antonino Neri, Antonio Palumbo, Roberto Piva

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Proteasome inhibitors (PI) are extensively used for the therapy of multiple myeloma (MM) and mantle cell lymphoma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. Here, to identify targets that synergize with PI, we carried out a functional screening in MM cell lines using a short hairpin RNA library against cancer driver genes. Isocitrate dehydrogenase 2 (IDH2) was identified as a top candidate, showing a synthetic lethal activity with the PI carfilzomib (CFZ). Combinations of US Food and Drug Administration–approved PI with a pharmacological IDH2 inhibitor (AGI-6780) triggered synergistic cytotoxicity in MM, mantle cell lymphoma, and Burkitt lymphoma cell lines. CFZ/AGI-6780 treatment increased death of primary CD138 1 cells from MM patients and exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone marrow–derived stromal cells. Mechanistically, the CFZ/AGI-6780 combination significantly decreased tricarboxylic acid cycle activity and adenosine triphosphate levels as a consequence of enhanced IDH2 enzymatic inhibition. Specifically, CFZ treatment reduced the expression of nicotinamide phosphoribosyltransferase (NAMPT), thus limiting IDH2 activation through the NAD 1 -dependent deacetylase SIRT3. Consistently, combination of CFZ with either NAMPT or SIRT3 inhibitors impaired IDH2 activity and increased MM cell death. Finally, inducible IDH2 knockdown enhanced the therapeutic efficacy of CFZ in a subcutaneous xenograft model of MM, resulting in inhibition of tumor progression and extended survival. Taken together, these findings indicate that NAMPT/SIRT3/IDH2 pathway inhibition enhances the therapeutic efficacy of PI, thus providing compelling evidence for treatments with lower and less toxic doses and broadening the application of PI to other malignancies.

Original languageEnglish
Pages (from-to)156-167
Number of pages12
JournalBlood
Volume133
Issue number2
DOIs
Publication statusPublished - Jan 10 2019

Fingerprint

Isocitrate Dehydrogenase
Proteasome Inhibitors
Hematologic Neoplasms
Multiple Myeloma
Nicotinamide Phosphoribosyltransferase
Mantle-Cell Lymphoma
Cytotoxicity
Therapeutics
Cells
Cell Line
Citric Acid Cycle
Burkitt Lymphoma
Poisons
Neoplasm Genes
Cell death
Stromal Cells
Heterografts
Pharmaceutical Preparations
NAD
Small Interfering RNA

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Bergaggio, E., Riganti, C., Garaffo, G., Vitale, N., Mereu, E., Bandini, C., ... Piva, R. (2019). IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. Blood, 133(2), 156-167. https://doi.org/10.1182/blood-2018-05-850826

IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. / Bergaggio, Elisa; Riganti, Chiara; Garaffo, Giulia; Vitale, Nicoletta; Mereu, Elisabetta; Bandini, Cecilia; Pellegrino, Elisa; Pullano, Verdiana; Omedè, Paola; Todoerti, Katia; Cascione, Luciano; Audrito, Valentina; Riccio, Anna; Rossi, Antonio; Bertoni, Francesco; Deaglio, Silvia; Neri, Antonino; Palumbo, Antonio; Piva, Roberto.

In: Blood, Vol. 133, No. 2, 10.01.2019, p. 156-167.

Research output: Contribution to journalArticle

Bergaggio, E, Riganti, C, Garaffo, G, Vitale, N, Mereu, E, Bandini, C, Pellegrino, E, Pullano, V, Omedè, P, Todoerti, K, Cascione, L, Audrito, V, Riccio, A, Rossi, A, Bertoni, F, Deaglio, S, Neri, A, Palumbo, A & Piva, R 2019, 'IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies', Blood, vol. 133, no. 2, pp. 156-167. https://doi.org/10.1182/blood-2018-05-850826
Bergaggio E, Riganti C, Garaffo G, Vitale N, Mereu E, Bandini C et al. IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. Blood. 2019 Jan 10;133(2):156-167. https://doi.org/10.1182/blood-2018-05-850826
Bergaggio, Elisa ; Riganti, Chiara ; Garaffo, Giulia ; Vitale, Nicoletta ; Mereu, Elisabetta ; Bandini, Cecilia ; Pellegrino, Elisa ; Pullano, Verdiana ; Omedè, Paola ; Todoerti, Katia ; Cascione, Luciano ; Audrito, Valentina ; Riccio, Anna ; Rossi, Antonio ; Bertoni, Francesco ; Deaglio, Silvia ; Neri, Antonino ; Palumbo, Antonio ; Piva, Roberto. / IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. In: Blood. 2019 ; Vol. 133, No. 2. pp. 156-167.
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AU - Bandini, Cecilia

AU - Pellegrino, Elisa

AU - Pullano, Verdiana

AU - Omedè, Paola

AU - Todoerti, Katia

AU - Cascione, Luciano

AU - Audrito, Valentina

AU - Riccio, Anna

AU - Rossi, Antonio

AU - Bertoni, Francesco

AU - Deaglio, Silvia

AU - Neri, Antonino

AU - Palumbo, Antonio

AU - Piva, Roberto

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N2 - Proteasome inhibitors (PI) are extensively used for the therapy of multiple myeloma (MM) and mantle cell lymphoma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. Here, to identify targets that synergize with PI, we carried out a functional screening in MM cell lines using a short hairpin RNA library against cancer driver genes. Isocitrate dehydrogenase 2 (IDH2) was identified as a top candidate, showing a synthetic lethal activity with the PI carfilzomib (CFZ). Combinations of US Food and Drug Administration–approved PI with a pharmacological IDH2 inhibitor (AGI-6780) triggered synergistic cytotoxicity in MM, mantle cell lymphoma, and Burkitt lymphoma cell lines. CFZ/AGI-6780 treatment increased death of primary CD138 1 cells from MM patients and exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone marrow–derived stromal cells. Mechanistically, the CFZ/AGI-6780 combination significantly decreased tricarboxylic acid cycle activity and adenosine triphosphate levels as a consequence of enhanced IDH2 enzymatic inhibition. Specifically, CFZ treatment reduced the expression of nicotinamide phosphoribosyltransferase (NAMPT), thus limiting IDH2 activation through the NAD 1 -dependent deacetylase SIRT3. Consistently, combination of CFZ with either NAMPT or SIRT3 inhibitors impaired IDH2 activity and increased MM cell death. Finally, inducible IDH2 knockdown enhanced the therapeutic efficacy of CFZ in a subcutaneous xenograft model of MM, resulting in inhibition of tumor progression and extended survival. Taken together, these findings indicate that NAMPT/SIRT3/IDH2 pathway inhibition enhances the therapeutic efficacy of PI, thus providing compelling evidence for treatments with lower and less toxic doses and broadening the application of PI to other malignancies.

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