Targeting transcription factors in multiple myeloma: evolving therapeutic strategies

ABSTRACT

Introduction: Transcription factors (TFs) are convergence points of signaling cascades that coordinate cell differentiation, proliferation, survival, and migration; and are commonly deregulated in solid and hematologic malignancies, including multiple myeloma (MM). Several recent studies indicate that the inhibition of TFs may lead to selective tumor cell death with little or no consequences for normal cells due to redundancy in signaling pathways. Nuclear hormone receptor (NHR)- TFs belong to the most common therapies in oncology today. In contrast, non-NHR-TFs have been considered ‘un- druggable’ until most recently.

Areas covered: This review article summarizes advances of our knowledge on the complex composition of non-NHR-TFs and their binding to cognate DNA sequences that are propelling the development of novel strategies in MM.

Expert opinion: Protein-protein and protein-DNA- binding inhibitors, proteolysis- targeting chimeric molecules, and chromatin remodeling/epigenetic reader inhibitors are among the most promising novel compounds with a potentially high therapeutic index; they are likely to once more advance MM treatment strategies and improve patient outcome in the near future.

KEYWORDS:

• Multiple myeloma
• transcription factors
• nuclear hormone receptor
• proteolysis targeting chimeric molecules
• plasma cells
• BET proteins
• germinal center
• somatic hypermutation
• class switch recombination

Article Highlights

• Transcription factors (TFs) are convergence points of signaling cascades that coordinate cell differentiation, proliferation, survival, and migration; and are commonly deregulated in solid and hematologic malignancies, including multiple myeloma (MM).

• Strategies to target TFs are a rapidly evolving field in MM drug discovery

• Besides direct modifications of TFs, extrinsic or intrinsic activation or inhibition of TFs via various signaling cascades within the BM microenvironment and epigenetic changes lead to MM cell development, proliferation, survival, migration and drug resistance.

• TFs are additionally associated with oncogenic addiction, the dependency on prolonged oncogene activity.

• Inhibition of TFs holds great therapeutic promise to selectively induce MM cell death and apoptosis and maybe even prevent tumor cell development without affecting healthy cells.

• Strategies to target TFs include: (1) inhibition of their expression; (2) the induction of their degradation; (3) the disruption of their interaction either with functionally critical protein binding partners or the DNA; and (4) the regulation of their binding at the epigenetic level by modulation of the chromatin accessibility

• Proteolysis- targeting chimera and chromatin remodeling/epigenetic reader inhibitors are among the most promising novel compounds

This box summarizes key points contained in the article.

Declaration of interest

S Vallet has received speaker’s honoraria from Pfizer and MSD and consultancy fees from Roche Pharmaceuticals. A Roccaro has received consultancy fees from Amgen and Janssen and research support from AstraZeneca. K Podar has received speaker’s honoraria from Celgene, Amgen Inc. and Janssen Pharmaceuticals, consultancy fees from Celgene and Janssen Pharmaceuticals, and research support from Roche Pharmaceuticals. S Lentzsch is a shareholder of Caelum Bioscinece and has received consultancy fees from Caelum Biosciences, Bayer, Abbvie, Janssen Pharmaceuticals, Proclara, and Takeda. SL receives research funding from Karyopharm and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded