Combining prenylation inhibitors causes synergistic cytotoxicity, apoptosis and disruption of RAS-to-MAP kinase signalling in multiple myeloma cells.
The high incidence of activating RAS mutations, coupled with accumulating evidence linking RAS to multiple myeloma (MM) pathogenesis, indicate that novel therapies utilising inhibitors of RAS prenylation and signalling may be successful in the management of this disease. While preclinical studies investigating prenylation inhibitors, such as lovastatin, farnesyltransferase inhibitors (FTI) and geranylgeranyltransferase inhibitors (GGTI), have been promising, recent phase I/II clinical trials with FTI R115777 were disappointing, suggesting resistance to FTI monotherapy. To address this issue, the effects of FTI, GGTI and lovastatin alone and in combination were analysed in MM cell lines and primary cells. FTI treatment blocked H-RAS processing, but was ineffective at inhibiting K- and N-RAS prenylation because of alternative geranylgeranylation of these isoforms. However, combinations of FTI and GGTI or lovastatin were found to synergistically inhibit MM cell proliferation, migration, K- and N-RAS processing, RAS-to-mitogen-activated protein kinase signalling and to induce apoptosis. In contrast to FTI, lovastatin and some GGTI were found to cause intracellular accumulation of Rho proteins. Our results suggest that clinical efficacy of prenylation inhibitors in MM are limited by alternative prenylation of several small G-proteins, such as RhoB, K- and N-RAS. Furthermore, strategies combining FTI with GGTI or statins may provide greater efficacy in MM treatment.
Morgan
Michael A
MA
Department of Haematology, Haemostaseology and Oncology, Hannover Medical School, Hannover, Germany.
Sebil
Tarkan
T
Aydilek
Erdem
E
Peest
Dietrich
D
Ganser
Arnold
A
Reuter
Christoph W M
CW
D000328:Adult; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D011905:Genes, ras; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D017368:Protein Prenylation / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008148:Lovastatin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D018631:ras Proteins