PLX311945

GSE94827: Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Multiple Myeloma (MM) is a frequently incurable hematological cancer in which over activity of MYC plays a central role, notably through upregulation 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, our most promising rocaglate. Proteome-wide, reversion correlated with selective depletion of short-lived proteins 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. SOURCE: Irene Ghobrial (irene_ghobrial@dfci.harvard.edu) - Ghobrial Lab Dana-Farber Cancer Institute