Molecular mechanisms of resistance to Rituximab and pharmacologic strategies for its circumvention

Research output: Contribution to journalReview articleContributedpeer-review

Contributors

  • Claudia Stolz - , Hematopoietic Stem Cell Laboratory, Lund Research Center for Stem Cell Biology and Cell Therapy, Lund University (Author)
  • Martin Schuler - (Author)

Abstract

The introduction of Rituximab has greatly improved therapeutic options for patients with B-cell non-Hodgkin lymphoma (B-NHL). However, a substantial fraction of patients with aggressive B-NHL fails first-line therapy, and most patients with relapsing indolent B-NHL eventually acquire Rituximab resistance. Molecular understanding of the underlying mechanisms facilitates the development of pharmacologic strategies to overcome resistance. Rituximab exerts its activity on CD20-expressing B-cells by indirect and direct effector mechanisms. Indirect mechanisms are complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Direct activities, such as growth inhibition, induction of apoptosis and chemosensitisation, have been reported, but are less defined. Moreover, the relative contribution of CDC, ADCC and direct mechanisms to the activity of Rituximab in vivo is unclear. Down-regulation of CD20 and expression of complement inhibitors have been described as escape mechanisms in B-NHL. Recent reports suggest that deregulated phosphoinositide-3-kinase (PI3K)/Akt, mitogen-activated kinases (MAPK) and nuclear-factor kappaB (NF-kappaB), as well as up-regulation of anti-apoptotic proteins may determine the efficacy of Rituximab to kill B-NHL cells in vitro and in vivo. The latter signalling pathways are attractive targets for pharmacologic modulation of resistance to Rituximab. With the advent of new inhibitors and antibodies, rationally designed clinical trials addressing Rituximab resistance are feasible.

Details

Original languageEnglish
Pages (from-to)873-85
Number of pages13
JournalLeukemia and lymphoma
Volume50
Issue number6
Publication statusPublished - Jun 2009
Peer-reviewedYes
Externally publishedYes

External IDs

Scopus 68449093749

Keywords

Keywords

  • Antibodies, Monoclonal/therapeutic use, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Agents/therapeutic use, Apoptosis/drug effects, Cell Cycle Proteins/metabolism, Drug Resistance, Neoplasm, Humans, Lymphoma, B-Cell/drug therapy, Models, Biological, Rituximab, Signal Transduction/drug effects