Transformation by Hras(G12V) is consistently associated with mutant allele copy gains and is reversed by farnesyl transferase inhibition.
RAS-driven malignancies remain a major therapeutic challenge. The two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) model of mouse skin carcinogenesis has been used to study mechanisms of epithelial tumor development by oncogenic Hras. We used mice with an Hras(G12V) knock-in allele to elucidate the early events after Hras activation, and to evaluate the therapeutic effectiveness of farnesyltransferase inhibition (FTI). Treatment of Caggs-Cre/FR-Hras(G12V) mice with TPA alone was sufficient to trigger papilloma development with a shorter latency and an ∼10-fold greater tumor burden than DMBA/TPA-treated WT-controls. Hras(G12V) allele copy number was increased in all papillomas induced by TPA. DMBA/TPA treatment of Hras(G12V) knock-in mice induced an even greater incidence of papillomas, which either harbored Hras(G12V) amplification or developed an Hras(Q61L) mutation in the second allele. Laser-capture microdissection of normal skin, hyperplastic skin and papillomas showed that amplification occurred only at the papilloma stage. HRAS-mutant allelic imbalance was also observed in human cancer cell lines, consistent with a requirement for augmented oncogenic HRAS signaling for tumor development. The FTI SCH66336 blocks HRAS farnesylation and delocalizes it from the plasma membrane. NRAS and KRAS are not affected as they are alternatively prenylated. When tested in lines harboring HRAS, NRAS or KRAS mutations, SCH66336 delocalized, inhibited signaling and preferentially inhibited growth only of HRAS-mutant lines. Treatment with SCH66336 also induced near-complete regression of papillomas of TPA-treated Hras(G12V) knock-in mice. These data suggest that farnesyl transferase inhibitors should be reevaluated as targeted agents for human HRAS-driven cancers, such as those of bladder, thyroid and other epithelial lineages.
Human Oncology and Pathogenesis Program, Sloan Kettering Cancer Center, New York, NY, USA.
X
X
Chen
Human Oncology and Pathogenesis Program, Sloan Kettering Cancer Center, New York, NY, USA.
J M
JM
Makarewicz
1] Human Oncology and Pathogenesis Program, Sloan Kettering Cancer Center, New York, NY, USA [2] Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
J A
JA
Knauf
Sloan Kettering Institute, New York, NY, USA.
L K
LK
Johnson
1] Human Oncology and Pathogenesis Program, Sloan Kettering Cancer Center, New York, NY, USA [2] Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA [3] Weill-Cornell Medical College, New York, NY, USA.
J A
JA
Fagin
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018628:Gene Dosage; D055879:Gene Knock-In Techniques; D011905:Genes, ras; D006801:Humans; D008817:Mice, Mutant Strains; D009154:Mutation; D010212:Papilloma / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D003986:Dibenzocycloheptenes
D015127:9,10-Dimethyl-1,2-benzanthracene; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D010880:Piperidines; D011725:Pyridines; D013755:Tetradecanoylphorbol Acetate; C115354:lonafarnib; D003986:Dibenzocycloheptenes