Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma

Yuan Xiao Zhu, K. Martin Kortuem, Alexander Keith Stewart

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance.

Original languageEnglish (US)
Pages (from-to)683-687
Number of pages5
JournalLeukemia and Lymphoma
Volume54
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Thalidomide
Multiple Myeloma
Pharmaceutical Preparations
Drug Resistance
Dissection
Cell Survival
Down-Regulation
Tumor Necrosis Factor-alpha
Biomarkers
T-Lymphocytes
Cell Line
lenalidomide
pomalidomide

Keywords

  • Cereblon
  • IMiDs
  • Myeloma

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. / Zhu, Yuan Xiao; Kortuem, K. Martin; Stewart, Alexander Keith.

In: Leukemia and Lymphoma, Vol. 54, No. 4, 04.2013, p. 683-687.

Research output: Contribution to journalArticle

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