Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay

The mevalonate pathway performs several key functions within cells leading to the production of sterols such as cholesterol essential to membrane formation, and to the post-translational modification by prenylation of proteins such as Ras and other small G proteins, which are important second messengers of growth signals from membrane growth factor receptors [1]. The process of prenylation involves farnesylation and geranylgeranylation from the mevalonate metabolite farnesyl pyrophosphate (FPP) as shown in figure 1. While farnesylation is usually required for translocation of Ras to the cell membrane during its activation [2], N-Ras and K-Ras can be geranylgeranylated in the presence of farnesyl transferase inhibitors (FTIs), providing a rationale for the limited clinical activity of these agents [3,4]. Ras signalling is essential to many cancers, either as part of activated growth receptor pathways or by the acquisition of activating mutations during carcinogenesis. There is therefore considerable interest in inhibiting the mevalonate pathway to treat cancers.The mevalonate pathway can be interrupted by existing drugs at several levels. As mevalonate is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), HMG-CoA inhibitors such as the statins reduce the entry of mevalonate into the pathway. This may explain the observed effects of statins, normally used to lower cholesterol levels, on the possible survival benefit in patients with non-small cell lung cancer (NSCLC) following chemotherapy [5], and other effects in a wide variety of tumour types. The newer N-bisphosphonates such as ibandronate (Roche) and zoledronic acid (Novartis) are inhibitors of farnesyl pyrophosphate (FPP) synthase, and therefore reduce the amount of both FPP and GGPP available for prenylation of Ras [6,7]. Growth inhibitory effects of these agents have been noted in cancer cell lines and in tumour-derived cells [7,8]. Finally, FTIs prevent the farnesylation of Ras and have effects