However, the inhibition of RAS protein function may still be important, particularly for tumours with mutant HRAS and tumours addicted to wild-type RAS

However, the inhibition of RAS protein function may still be important, particularly for tumours with mutant HRAS and tumours addicted to wild-type RAS. activating oncogenic mutations in the genes (between 8% and 93%, depending on the tumour type)1, and that RAS GTPases require this lipid post-translational modification (PTM) for their malignant transforming activity2. Furthermore, many of the signal transduction pathways that are activated by RAS involve proteins that require farnesylation or geranylgeranylation (together referred to as prenylation) for their ability to mediate tumour cell survival, growth, proliferation, migration and metastasis (FIG. 1). This, coupled with the fact that it has notoriously been difficult to design small GTPase inhibitors per se3, prompted a global quest to develop farnesyltransferase Inulin (FT) inhibitors (FTIs) and geranylgeranyltransferase 1 (GGT1) inhibitors (GGTIs) (together referred to as prenyltransferase (PT) inhibitors (PTIs)) as potential anticancer drugs. Open in a separate window Figure 1 RAS signalling pathways in mammalian cellsActive (farnesylated, membrane-bound and GTP-bound) RAS Inulin modulates a number of signalling pathways. Oncogenic RAS mutations tend to lock RAS in its GTP-bound state, resulting in constitutive RAS signalling. The major RAS effector pathways are shown. The two best-studied pathways that are activated by RAS are the RAFCMEKCMAPK signalling cascade and the PI3KCAKT pathway. The RAFCMEKCMAPK pathway ultimately activates the ETS family of transcription factors, which induce multiple genes that promote cell cycle progression and cell migration. Likewise, AKT phosphorylates multiple cellular proteins, leading to the inhibition of several tumour suppressors (such as p27, p53, tuberous sclerosis 1 (TSC1), TSC2 and BCL-2 antagonist of cell death (BAD)) or leading to the activation of several oncogene products. RAS also activates other small GTPases such as Inulin RALA and RALB, which have recently been shown to mediate RAS transformation in human pancreatic tumours, for example. Farnesyltransferase inhibitors (FTIs) were originally developed to block the function of RAS. However, as numerous studies and have shown, their antitumour activity is not correlated to the mutation status of KRAS isoforms. This suggests that the antitumour activity of FTIs relies on blocking the activity of other prenylated proteins. However, the Inulin inhibition of RAS protein function may still be important, particularly for tumours with mutant HRAS and tumours addicted to wild-type RAS. CDC42, cell division cycle 42; DAG, diacylglycerol; FOX, forkhead transcription factor; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; IKK, IB kinase; IP3, inositol-1,4,5-trisphosphate; mTORC, mTOR complex; NF-B, nuclear Inulin factor-B; PDK1, phosphoinositide-dependent kinase 1; PKC, protein kinase C; PLA, phospholipase A; PLC, phospholipase C; PLD, phospholipase D; RALGDS, RAL guanine nucleotide dissociation stimulator; RHEB, RAS homologue enriched in brain; RIN1, RAS and RAB interactor 1; TIAM1, T cell lymphoma invasion and metastasis 1. Preclinical studies in the 1990s demonstrated that FTIs are highly successful in killing cancer cells and in animals with very little toxicity, thus generating much excitement and raising the hope that, finally, a RAS inhibitor may be developed as a novel anticancer drug. Contrary to expectations, however, responses to FTIs, whether in cells, animals or human patients, do not seem to depend on mutations; and the inhibition of KRAS farnesylation leads Rabbit Polyclonal to Notch 2 (Cleaved-Asp1733) to its geranylgeranylation (discussed below). Furthermore, in most clinical trials FTIs have not been as successful as expected, with no survival advantages, for example, to patients with advanced solid cancers4C6 or with acute myeloid leukaemia (AML)7. However, monotherapy with FTIs demonstrates antitumour activity in a subset of cancer patients, particularly those with haematological malignancies, whereas combinations of FTIs with cytotoxic agents improve the responses of patients with locally advanced breast cancer or other advanced solid tumours8C11. At present, we do not understand why some tumours are resistant while others are sensitive to FTIs. Clearly, the identification of the farnesylated proteins the inhibition.