Title:Targeting of NF-kappaB Signaling Pathway, other Signaling Pathways and Epigenetics in Therapy of Multiple Myeloma
VOLUME: 13 ISSUE: 1
Author(s):Ota Fuchs
Affiliation:Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague 2, Czech Republic.
Keywords:Multiple myeloma, NF-κB, IκBα, MEK/MAPK, PI3K/Akt/mTOR, apoptosis.
Abstract:Multiple myeloma (MM) remains an incurable disease, at least for the big majority of patients, in spite of the
great progress with new drugs in the last years. New treatment strategies are needed to improve the outcome of patients.
NF-κB activation in MM is caused by mutations in the factors involved in the NF-κB pathways contributing to their
dysregulation and by signals from the bone marrow microenvironment. Agents with NF-κB inhibitory activity enhance
the anti-MM effects of conventional chemotherapeutic agents. Bortezomib was the first approved member of a new class
of anti-MM agents, the proteasome inhibitors. At least, five proteasome inhibitors of the next generation with greater
efficacy (carfilzomib, marizomib (salinosporamide A, NPI-0052), threonine boronic acid-derived proteasome inhibitor
CEP-18770, the peptide-semicarbazone S-2209, the tripeptide mimetic BSc2118, and MLN9708/2238) have been recently
tested in preclinical models of MM. Carfilzomib has been recently approved for the treatment of patients with MM who
have received at least two prior therapies, including bortezomib and immunomodulatory derivatives (IMiDs, thalidomide,
lenalidomide or pomalidomide). More specific IκB kinase inhibitors were also used in preclinical studies. The analysis of
MM genomes revealed also mutations in genes for histone methyltransferases (HMTases), histone demethylase (UTX)
and serine/threonine protein kinase BRAF. Aberrant histone 3 lysine 27 trimethylation (H3K27me3) by mutant HMTases
or UTX induces overexpression of the homeobox A9 (HOXA9) gene. HOXA9 is normally expressed in primitive bone
marrow cells and is silenced when cells differentiate. HOXA9 is a MM oncogene and targeting of its expression by histone
deacetylases inhibitors or by a phosphoinositide 3-kinase (PI3K) inhibitors through an epigenetic mechanism involving
H3K27me3. Mutant BRAF kinase small-molecule, ATP-competitive, a highly selective, potent and orally bioavailable
inhibitors (GDC-0879, PLX 4032 and PLX 4720) are already under investigation and PLX 4032 is in phase II and phase
III clinical trials. Two key signaling pathways involved in the regulation of MM cell growth are the Ras/Raf/MEK/ERK
and PI3K/Akt/mTOR pathways and their inhibition are anti-proliferative and pro-apoptotic and can overcome the
development of resistance to common drugs.
