Abstract 4290: The farnesyl transferase inhibitor SCH 66336 induces regression of Hras-driven tumors in mice with widespread endogenous expression of HrasG12V

We previously reported that mice with a knock-in HrasG12V allele (Caggs-Cre/FR-HrasG12V) develop skin and forestomach papillomas as well as angiosarcomas with a relatively long latency. In these mice, activation of a single Hras mutant allele was not sufficient for transformation. 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. Although DMBA-induced HrasQ61L mutations are implicated in tumor formation in this model, it is not clear whether Hras is a tumor initiator, and whether its activity is required for tumor maintenance. To further clarify the role of the Hras gene in the DMBA/TPA model, we treated the skin of HrasG12V mice with the TPA tumor promoter alone, and found that this was sufficient to trigger rapid papilloma development. Latency was shorter, and tumor burden ∼ 10-fold greater than in DMBA/TPA treated WT controls. The mutant Hras allele copy number was increased in all 10 papillomas induced by TPA alone. Interestingly, DMBA/TPA treatment of HrasG12V mice induced an even greater incidence of papillomas: whereas 7/10 randomly selected papillomas induced by DMBA/ TPA in HrasG12V mice had amplified the HrasG12V allele, the remaining 3 had acquired an HrasQ61L mutation in the second Hras allele. Laser-capture microdissection of normal, hyperplastic and papilloma tissues from TPA-treated HrasG12V mice showed that Hras mutant allele amplification occurred only at the papilloma stage. Moreover, HRAS allelic imbalance was also observed in several human cancer cell lines with HRAS mutation (Hth83, C643 and T24). These data indicate that oncogenic Hras is a tumor initiator, and that augmentation of oncogenic Hras signaling is likely required for tumor formation through increased mutant Hras copy number or through mutation in the second Hras allele. SCH66336 is a farnesyl transferase inhibitor (FTI) that blocks the farnesylation of Hras, resulting in Hras delocalization from the plasma membrane. All Ras isoforms are farnesylated, however, upon treatment with FTI, Nras and Kras, but not Hras, are alternatively prenylated by geranylgeranylprenyltransferase-1. When tested in human cell lines harboring HRAS, NRAS or KRAS mutations, the FTI SCH 66336 delocalized only the Hras protein, inhibited its downstream signaling, and preferentially inhibited growth of HRAS-mutant lines. Treatment of TPA-treated HrasG12V mice with SCH 66336 (80mg/kg, b.i.d PO) induced an almost complete regression of Hras-driven papillomas within 10 days. The mechanism by which SCH66336 induced dramatic papilloma regression is under investigation. These observations suggest that FTIs should be re-evaluated as a therapy for human HRAS-driven cancers, such as those of bladder, thyroid and other epithelial lineages. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4290. doi:10.1158/1538-7445.AM2011-4290