Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma.
Multiple myeloma (MM) is an invariably fatal form of cancer characterized by clonal proliferation of malignant plasma cells in the bone marrow. The canonical Wnt signaling pathway is activated in MM cells through constitutively active beta-catenin, a messenger molecule relevant to growth, survival, and migration of MM cells. The identification of a number of small molecular compounds, such as PKF115-584, which disrupt the interaction of the transcriptionally active beta-catenin/TCF protein complex, provides valuable new therapeutic tools to target an alternative pathway in MM independent of the proteasome. Here we evaluated the transcriptional, proteomic, signaling changes, and biological sequelae associated with the inhibition of Wnt signaling in MM by PKF115-584. The compound blocks expression of Wnt target genes and induces cytotoxicity in both patient MM cells and MM cell lines without a significant effect in normal plasma cells. In xenograft models of human MM, PKF115-584 inhibits tumor growth and prolongs survival. Taken together, these data demonstrate the efficacy of disrupting the beta-catenin/TCF transcriptional complex to exploit tumor dependence on Wnt signaling as a therapeutic approach in the treatment of MM.
Sukhdeo
Kumar
K
Department of Medical Oncology, Harvard Medical School, Boston, MA 02115, USA.
Mani
Mala
M
Zhang
Yunyu
Y
Dutta
Jui
J
Yasui
Hiroshi
H
Rooney
Melissa D
MD
Carrasco
Daniel E
DE
Zheng
Mei
M
He
Haiying
H
Tai
Yu-Tzu
YT
Mitsiades
Constantine
C
Anderson
Kenneth C
KC
Carrasco
Daniel R
DR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding; D015398:Signal Transduction; D015996:Survival Rate; D051820:TCF Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015850:Interleukin-6; C538949:PKF115-584; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D010569:Perylene