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

D. Cirstea, T. Hideshima, L. Santo, H. Eda, Y. Mishima, N. Nemani, Y. Hu, N. Mimura, F. Cottini, G. Gorgun, H. Ohguchi, R. Suzuki, H. Loferer, N. C. Munshi, K. C. Anderson, N. Raje

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2366-2375
Number of pages10
JournalLeukemia
Volume27
Issue number12
DOIs
StatePublished - Dec 1 2013

Keywords

  • CDKs
  • apoptosis
  • myeloma
  • p53
  • transcription

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Cirstea, D., Hideshima, T., Santo, L., Eda, H., Mishima, Y., Nemani, N., Hu, Y., Mimura, N., Cottini, F., Gorgun, G., Ohguchi, H., Suzuki, R., Loferer, H., Munshi, N. C., Anderson, K. C., & Raje, N. (2013). Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and-independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia, 27(12), 2366-2375. https://doi.org/10.1038/leu.2013.194