Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors.

Publikation

Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors.

Wissenschaftlicher Artikel/Review - 03.01.2019

Besse Andrej, Besse Lenka, Kraus Marianne, Mendez Lopez Max, Bader Jürgen, Xin Bo-Tao, de Bruin Gerjan, Maurits Elmer, Overkleeft Hermann S, Driessen Christoph

Zitation

Besse A, Besse L, Kraus M, Mendez Lopez M, Bader J, Xin B, de Bruin G, Maurits E, Overkleeft H, Driessen C. Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors. Cell Chem Biol 2019; 26:340-351.e3.

Art

Wissenschaftlicher Artikel/Review (Englisch)

Zeitschrift

Cell Chem Biol 2019; 26

Veröffentlichungsdatum

03.01.2019

eISSN (Online)

2451-9448

Seiten

340-351.e3

Kurzbeschreibung/Zielsetzung

Proteasome inhibitors (PIs) are a backbone of multiple myeloma (MM) therapy. The proteasome harbors six proteolytically active subunits (β1, β2, β5), while β5 was identified as rate-limiting and is a primary target of clinically available PIs. The most effective pattern of subunit inhibition provided by these PIs for cytotoxic activity in MM is unknown. A head-to-head comparison of clinically available PIs shows that in the clinically relevant setting only the co-inhibition of β1 or β2 with β5 activity achieves meaningful functional proteasome inhibition and cytotoxicity, while the selective β2/β5 inhibition of both constitutive and immunoproteasome is the most cytotoxic. In the long-term setting, selective inhibition of β5 subunit is sufficient to induce cytotoxicity in PI-sensitive, but not in PI-resistant MM, and the β5/β2 co-inhibition is the most cytotoxic in PI-resistant MM. These results give a rational basis for selecting individual PIs for the treatment of MM.