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Myeloma

Small-molecule multi-_targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs

Leukemia volume 27, pages 2366–2375 (2013)Cite this article

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Abstract

Small-molecule multi-_targeted cyclin-dependent kinase (CDK) inhibitors (CDKIs) are of particular interest due to their potent antitumor activity independent of p53 gene alterations. P53 deletion is associated with a very poor prognosis in multiple myeloma (MM). In this regard, we tested the anti-MM activity of RGB-286638, an indenopyrazole-derived CDKI with Ki-nanomolar activity against transcriptional CDKs. We examined RGB-286638’s mode-of-action in MM cell lines with wild-type (wt)-p53 and those expressing mutant p53. RGB-286638 treatment resulted in MM cytotoxicity in vitro associated with inhibition of MM tumor growth and prolonged survival in vivo. RGB-286638 displayed caspase-dependent apoptosis in both wt-p53 and mutant-p53 cells that was closely associated with the downregulation of RNA polymerase II phosphorylation and inhibition of transcription. RGB-286638 triggered p53 accumulation via nucleolar stress and loss of Mdm2, accompanied by induction of p53 DNA-binding activity. In addition, RGB-286638 mediated p53-independent activity, which was confirmed by cytotoxicity in p53-knockdown and p53-mutant cells. We also demonstrated downregulation of oncogenic miR-19, miR-92a-1 and miR-21. Our data provide the rationale for the development of transcriptional CDKIs as therapeutic agents, which activate p53 in competent cells, while circumventing p53 deficiency through alternative p53-independent cell death mechanisms in p53-mutant/deleted cells.

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Acknowledgements

This study was supported by Grant CDA SPORE and NIH/NCI Grant no. P50 CA100707. RGB-286638 compound was provided by Agennix USA Inc.

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Authors and Affiliations

  1. MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    D Cirstea, L Santo, H Eda, Y Mishima, N Nemani & N Raje

  2. Leebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Boston, MA, USA

    D Cirstea, T Hideshima, Y Hu, N Mimura, F Cottini, G Gorgun, H Ohguchi, R Suzuki, N C Munshi, K C Anderson & N Raje

  3. Project Management, Agennix, AG, Germany

    H Loferer

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  1. D Cirstea
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Correspondence to N Raje.

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Competing interests

Hannes Loferer is the Agennix AG employee. The remaining authors declare no conflict of interest.

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Cirstea, D., Hideshima, T., Santo, L. et al. Small-molecule multi-_targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia 27, 2366–2375 (2013). https://doi.org/10.1038/leu.2013.194

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