In Vitro and In Vivo Selective Antitumor Activity of a Novel Orally Bioavailable Proteasome Inhibitor MLN9708 against Multiple Myeloma Cells

Abstract

Purpose The success of bortezomib therapy for treatment of multiple myeloma (MM) led to the development of structurally and pharmacologically distinct novel proteasome inhibitors. In the present study, we evaluated the efficacy of one such novel orally bioactive proteasome inhibitor MLN9708/MLN2238 in MM using well-established in vitro and in vivo models. Experimental Design MM cell lines, primary patient cells, and the human MM xenograft animal model were utilized to study the antitumor activity of MN2238. Results Treatment of MM cells with MLN2238 predominantly inhibits chymotrypsin-like activity of the proteasome and induces accumulation of ubiquitinated proteins. MLN2238 inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies without affecting the viability of normal cells. In animal tumor model studies, MLN2238 is well tolerated and inhibits tumor growth with significantly reduced tumor recurrence. A head-to-head analysis of MLN2238 versus bortezomib showed a significantly longer survival time in mice treated with MLN2238 than mice receiving bortezomib. Immununostaining of MM tumors from MLN2238-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Mechanistic studies showed that MLN2238-triggered apoptosis is associated with activation of caspase-3, caspase-8, and caspase-9; increase in p53, p21, Noxa, PUMA, and E2F; induction of ER stress response proteins Bip, phospho-eIF2-α, and CHOP; and inhibition of NF-κB. Finally, combining MLN2238 with lenalidomide, HDAC inhibitor SAHA or dexamethasone triggers synergistic anti-MM activity. Conclusion Our preclinical study supports clinical evaluation of MLN9708, alone or in combination, as a potential MM therapy.

Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma

“…30 Ixazomib has demonstrated antitumor activity in a range of tumor xenograft models, including MM models. [30][31][32][33] Preclinical studies have shown activity in myeloma cells resistant to bortezomib. 31 Additionally, ixazomib has shown synergistic antimyeloma activity combined with dexamethasone and lenalidomide in preclinical studies.…”

“…[30][31][32][33] Preclinical studies have shown activity in myeloma cells resistant to bortezomib. 31 Additionally, ixazomib has shown synergistic antimyeloma activity combined with dexamethasone and lenalidomide in preclinical studies. 31 These encouraging preclinical data formed the basis for clinical evaluation of ixazomib.…”

Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy

“…For instance, MLN 2238 was shown to induce apoptosis in bortezomib-resistant MM cells. 13 Carfilzomib in combination with marizomib (NPI-0052) was also found to induce cell death in MM cells that were derived from bortezomib refractory patients. 14,15 In a separate study, the PI delanzomib had anti-MM effects in bortezomib-resistant MM, and the combination of delanzomib and bortezomib was found to have greater anti-MM activity compared with either agent alone.…”

The next generation of novel therapies for the management of relapsed multiple myeloma

“…Like bortezomib, it also inhibits the 20S proteasome complex reversibly [18]. However, it has a faster dissociation rate from the proteasome compared with bortezomib, and preclinical studies demonstrate its cytotoxic activity in MM cell lines resistant to bortezomib [19].…”