RT Journal Article
SR Electronic
T1 Janus kinase inhibitor INCB20 has antiproliferative and apoptotic effects on human myeloma cells <em>in vitro</em> and <em>in vivo</em>
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 26
OP 35
DO 10.1158/1535-7163.MCT-08-0149
VO 8
IS 1
A1 Burger, Renate
A1 Le Gouill, Steven
A1 Tai, Yu-Tzu
A1 Shringarpure, Reshma
A1 Tassone, Pierfrancesco
A1 Neri, Paola
A1 Podar, Klaus
A1 Catley, Laurence
A1 Hideshima, Teru
A1 Chauhan, Dharminder
A1 Caulder, Eian
A1 Neilan, Claire L.
A1 Vaddi, Kris
A1 Li, Jun
A1 Gramatzki, Martin
A1 Fridman, Jordan S.
A1 Anderson, Kenneth C.
YR 2009
UL http://mct.aacrjournals.org/content/8/1/26.abstract
AB Protein tyrosine kinases of the Janus kinase (JAK) family are associated with many cytokine receptors, which, on ligand binding, regulate important cellular functions such as proliferation, survival, and differentiation. In multiple myeloma, JAKs may be persistently activated due to a constant stimulation by interleukin (IL)-6, which is produced in the bone marrow environment. INCB20 is a synthetic molecule that potently inhibits all members of the JAK family with a 100- to 1,000-fold selectivity for JAKs over &gt;70 other kinases. Treatment of multiple myeloma cell lines and patient tumor cells with INCB20 resulted in a significant and dose-dependent inhibition of spontaneous as well as IL-6-induced cell growth. Importantly, multiple myeloma cell growth was inhibited in the presence of bone marrow stromal cells. The IL-6 dependent cell line INA-6 was particularly sensitive to the drug (IC50 &lt; 1 μmol/L). Growth suppression of INA-6 correlated with an increase in the percentage of apoptotic cells and inhibition of signal transducer and activator of transcription 3 phosphorylation. INCB20 also abrogated the protective effect of IL-6 against dexamethasone by blocking phosphorylation of SHP-2 and AKT. In contrast, AKT phosphorylation induced by insulin-like growth factor-I remained unchanged, showing selectivity of the compound. In a s.c. severe combined immunodeficient mouse model with INA-6, INCB20 significantly delayed INA-6 tumor growth. Our studies show that disruption of JAKs and downstream signaling pathways may both inhibit multiple myeloma cell growth and survival and overcome cytokine-mediated drug resistance, thereby providing the preclinical rationale for the use of JAK inhibitors as a novel therapeutic approach in multiple myeloma. [Mol Cancer Ther 2009;8(1):26–35]