Small Molecule Multi-Targeted Kinase Inhibitor RGB-286638 Triggers P53-Dependent and -Independent Anti-Multiple Myeloma Activity through Inhibition of Transcriptional CDKs

Cirstea, DianaHideshima, TeruSanto, LoredanaEda, HomareMishima, YukoNemani, NeeharikaHu, YiguoMimura, NaoyaCottini, FrancescaGorgun, GulluOhguchi, HirotoSuzuki, RikioLoferer, HannesMunshi, Nikhil C.Anderson, Kenneth C.Raje, Noopur2014-07-072014Cirstea, D., T. Hideshima, L. Santo, H. Eda, Y. Mishima, N. Nemani, Y. Hu, et al. 2014. “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. doi:10.1038/leu.2013.194. http://dx.doi.org/10.1038/leu.2013.194.0887-6924http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406716Small molecule multi-targeted 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. Additionally, 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 CDK inhibitors 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.en-USmyelomap53transcriptionCDKsapoptosisSmall Molecule Multi-Targeted Kinase Inhibitor RGB-286638 Triggers P53-Dependent and -Independent Anti-Multiple Myeloma Activity through Inhibition of Transcriptional CDKsJournal Article2014-07-0710.1038/leu.2013.194