Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

Abstract

Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates.

Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen Candida auris

“…Phenotypes associated with apoptosis could be a consequence of translation inhibition causing rapid depletion of one or more short-lived antiapoptotic proteins which then allows initiation of an active cell death program. Consistent with this model, the induction of programmed cell death by rocaglates in cancer cells (57,59,60) is thought to be driven at least in part by a dramatic reduction in the levels of short-lived prosurvival proteins such as MCL-1, MDM2, and BCL-xL (59,61). In certain malignancies, this proapoptotic effect is amplified by the fact that unlike translation elongation inhibitors, rocaglates selectively reduce the production of proteins that require eIF4A for synthesis due to their long, highly structured 5= UTR's.…”

“…In mammalian cells, highly eIF4A-dependent proteins include MYC, MDM2, and cyclins, all of which promote malignant transformation. Thus, in cancers, rocaglates not only trigger apoptosis but also impair translation of oncogenic drivers (61). In the context of C. auris, it remains to be explored whether rocaglate-induced cell death is also due to depletion of specific proteins or if it is attributable more broadly to activation of starvation responses as a consequence of impaired protein synthesis.…”

Clinical prognostic implications of EPB41L4A expression in multiple myeloma

“…(46-48) High expression of CCND1 can make MM patients have a better prognosis by highly specific inhibition of translation of myeloma cells. (49,50) However, CCND1 is also involved in the most common translocation in myeloma (11; 14). The translocation (11; 14) placed CCND1 under the transcriptional control of the immunoglobulin heavy chain (IgH) enhancer, resulting in a dysregulation of CCND1, thereby accelerating the G1 to S phase transition in the plasma cell.…”

Pathogenesis and therapeutic targeting of aberrant MYC expression in haematological cancers

“…Ribosomal biogenesis, translation initiation factors and RNA polymerase, among other key aspects of protein biosynthesis, are directly regulated by MYC (van Riggelen et al , ). Also, inhibitions of translation initiation and RNA polymerase have been shown to directly affect MYC expression (Lee et al , ; Manier et al , ). The phosphoinositide‐3‐kinase (PI3K)‐mammalian/mechanistic target of rapamycin (MTOR) axis, including its downstream effector initiation factor of translation (EIF4E), is known to be an essential regulator of translation and strongly cooperates with MYC (Ruggero et al , ; Sander et al , ).…”