Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer

• RAS and RHO proteins, which contribute to tumorigenesis and metastasis, undergo posttranslational modification with an isoprenyl lipid by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase-I (GGTase-I). Inhibitors of FTase and GGTase-I were developed to block RAS-induced malignancies, but their utility has been difficult to evaluate because of off-target effects, drug resistance, and toxicity. Moreover, the impact of FTase deficiency and combined FTase/GGTase-I deficiency has not been evaluated with genetic approaches. We found that inactivation of FTase eliminated farnesylation of HDJ2 and H-RAS, prevented H-RAS targeting to the plasma membrane, and blocked proliferation of primary and K-RAS(G12D)-expressing fibroblasts. FTase inactivation in mice with K-RAS-induced lung cancer reduced tumor growth and improved survival, similar to results obtained previously with inactivation of GGTase-I. Simultaneous inactivation of FTase and GGTase-I markedly reduced lung tumors and improved survival without apparent pulmonary toxicity. These data shed light on the biochemical and therapeutic importance of FTase and suggest that simultaneous inhibition of FTase and GGTase-I could be useful in cancer therapeutics.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Alkyl and Aryl Transferases/genetics/metabolism

Alleles

Animals

Cell Proliferation

Cell Transformation

Neoplastic/genetics/*metabolism

Dimethylallyltranstransferase/deficiency/*metabolism

Disease Models

Animal

Gene Expression Regulation

Enzymologic

Gene Expression Regulation

Neoplastic

Lung Neoplasms/*enzymology/genetics/pathology/therapy

Mice

Mice

Knockout

Mutation

Proto-Oncogene Proteins p21(ras)/genetics/*metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)