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Myeloma

MRK003, a γ-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin's lymphoma

Abstract

Notch-stimulated signaling cascade results in transcriptional regulation of genes involved in cell fate decision, apoptosis and proliferation and has been implicated in various malignancies. Here, we investigated the impact of MRK003, an inhibitor of this pathway, on myeloma and lymphoma cells. We first studied the expression patterns of notch receptors and ligands on multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Next, we used a γ-secretase inhibitor, MRK003 to test the importance of notch-stimulated pathways in MM and NHL disease biology. We observed expression of notch receptors and ligands on MM and NHL cell lines. MRK003 treatment induced caspase-dependent apoptosis and inhibited proliferation of MM and NHL cell lines and patient cells. Examination of signaling events after treatment showed time-dependent decrease in levels of the notch intracellular domain, Hes1 and c-Myc. MRK003 downregulated cyclin D1, Bcl-Xl and Xiap levels in NHL cells and p21, Bcl-2 and Bcl-Xl in MM cells. In addition, MRK003 caused an upregulation of pAkt, indicating crosstalk with the PI3K/Akt pathway. We evaluated MRK003 in combination with Akt1/2 kinase inhibitor and observed synergy in killing MM and NHL cell lines examined.

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Acknowledgements

We acknowledge Kimberly Henderson, Roberta DeGoey and Steven Zincke for their assistance with processing of tumor cells and all of the patients who provided us with the tumor samples. This study was supported in part by the Hematological Malignancies Program (Mayo Clinic Cancer Center) and CA90628 (SK) from National Cancer Institute.

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Correspondence to S Kumar.

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SK received research support from Celgene, Millennium, Novartis, Merck and Co. Inc., Cephalon, Genzyme and Bayer. SK is also on the advisory board of Merck and Co. Inc.

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Ramakrishnan, V., Ansell, S., Haug, J. et al. MRK003, a γ-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin's lymphoma. Leukemia 26, 340–348 (2012). https://doi.org/10.1038/leu.2011.192

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