Farnesyl transferase inhibitors--a novel therapy for breast cancer.

Johnston, Stephen; Kèlland, Lloyd R.

doi:10.1677/erc.0.0080227

Cited by 36 publications

(37 citation statements)

References 30 publications

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“…While ras mutations are not as common in breast cancer as in some other types of malignancy, the increased activity of growth factor signalling pathways which are mediated via Ras proteins makes targeting Ras action an attractive option in breast cancer treatment. By preventing maturation into its biologically active form, farnesyl transferase inhibitors (FTIs) abolish the membrane localisation (Lerner et al, 1995) and function of Ras (Nagase et al, 1996) and these agents are currently under evaluation in clinical trials in patients with breast cancer (Johnston and Kelland, 2001). We have determined if N-BPs can also prevent Ras processing leading to its cytoplasmic accumulation.…”

Section: Discussionmentioning

confidence: 99%

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Mansi

2002

Br J Cancer

128

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Bisphosphonates are well established in the management of cancer-induced bone disease. Recent studies have indicated that these compounds have direct inhibitory effects on cultured human breast cancer cells. Nitrogen-containing bisphosphonates including zoledronic acid have been shown to induce apoptosis associated with PARP cleavage and DNA fragmentation. The aim of this study was to identify the signalling pathways involved. Forced expression of the anti-apoptotic protein bcl-2 attenuated bisphosphonate-induced loss of cell viability and induction of DNA fragmentation in MDA-MB-231 cells. Zoledronic acid-mediated apoptosis was associated with a time and dose-related release of mitochondrial cytochrome c into the cytosol in two cell lines. Rescue of cells by preincubation with a caspase-3 selective inhibitor and demonstration of procaspase-3 cleavage products by immunoblotting suggests that at least one of the caspases activated in response to zoledronic acid treatment is caspase-3. In both MDA-MB-231 and MCF-7 breast cancer cells, zoledronic acid impaired membrane localisation of Ras indicating reduced prenylation of this protein. These observations demonstrate that zoledronic acidmediated apoptosis is associated with cytochrome c release and consequent caspase activation. This process may be initiated by inhibition of the enzymes in the mevalonate pathway leading to impaired prenylation of key intracellular proteins including Ras.

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Section: Discussionmentioning

confidence: 99%

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Mansi

2002

Br J Cancer

128

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“…The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways (Johnston & Kelland 2001) and, as such, provide a rational target for the treatment of malignancies. Farnesyl transferase inhibitors (FTIs) are a group of agents that target the ras family and its downstream signaling pathways, and are being evaluated in phase I, II and III trials in a number of malignancies (Johnston & Kelland 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Farnesyl transferase inhibitors (FTIs) are a group of agents that target the ras family and its downstream signaling pathways, and are being evaluated in phase I, II and III trials in a number of malignancies (Johnston & Kelland 2001). Unlike, many other solid tumors, breast cancers have a very low rate of ras mutations (Clark & Der 1995a).…”

Section: Introductionmentioning

confidence: 99%

Farnesyl transferase inhibitors: the next targeted therapies for breast cancer?

O’Regan¹,

Khuri²

2004

Endocr Relat Cancer

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The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways involved in cell proliferation and survival. Point mutations of ras oncogenes result in constitutively active Ras and have been shown to be oncogenic. However, ras activation can occur in the absence of ras mutations secondary to upstream receptor activation. The first important step in Ras activation is farnesylation by farnesyl transferase, and inhibitors of this enzyme have been demonstrated to inhibit Ras signaling, and have anti-tumor effects. However, it is now clear that farnesyl transferase inhibitors (FTIs) have activity independent of Ras, most likely due to effects on prenylated proteins downstream of Ras, which explains their activity in several malignancies, including breast cancer, where ras mutations are rare. Several FTIs are in clinical development for the treatment of solid tumors. Preclinical evidence suggests that FTIs can inhibit breast cancers in vitro and in vivo, and a phase II trial of the FTI, R115777, in patients with advanced breast cancer produced encouraging results. Based on prior successful outcomes with agents targeting the estrogen and epidermal growth factor receptor pathways in breast cancer, the FTIs, used alone or more likely with other agents, may be the next exciting targeted therapy in breast cancer.

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“…farnesyltransferase inhibitors (FTIs) are an example of this approach. Farnesylation is a posttranslation lipid modification that is vital for the function of several proteins critical to cell signaling and proliferation [38]. It was originally proposed that FTIs would operate by inactivating the Ras-dependent growth factor receptor pathway because a farnesyl moiety had been shown to be critical for anchoring Ras and Ras-like G proteins to the inner aspect of the plasma membrane [39].…”

Section: Other Approaches To Endocrine Therapy Resistance-farnesyltramentioning

confidence: 99%

Overcoming Endocrine Therapy Resistance by Signal Transduction Inhibition

Ellis

2004

The Oncologist

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Endocrine therapy is the most effective systemic treatment for patients with hormone-receptor-positive (HR + ) breast cancer. Unfortunately, efficacy is often limited by the onset of resistance, which is almost inevitable for patients with advanced disease. Several patterns of endocrine resistance are recognizable clinically, including: A) tumors that are inherently insensitive to all attempts at estrogen receptor (ER) targeting despite expression of ER (pan-endocrine therapy resistance); B) tumors that are estrogen dependent but resistant to one or more specific endocrine therapies (agent-selective resistance); and C) tumors that initially respond but subsequently progress (acquired resistance). Current insights into the molecular basis for these resistance patterns are rudimentary, but are most clearly illuminated by investigations that focus on the crosstalk between the ErbB or HER peptide growth factor family and the ER. The data are sufficiently compelling to be addressed by ongoing clinical trials that examine combinations of endocrine agents and either trastuzumab Medicine, 660 South Euclid Avenue, Campus Box 8056, Division of Oncology, St. Louis, Missouri 63110, USA. Telephone: 314-362-8866; Fax: 314-362-7086; e-mail: mellis@im.wustl.edu Received March 26, 2004; accepted for publication April 15, 2004. ©AlphaMed Press 1083-7159/2004 The Oncologist ® LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Discuss patterns of resistance to endocrine therapy for breast cancer.2. Relate differences in resistance patterns in early and advanced disease settings.3. Identify potential treatment strategies to overcome resistance and/or restore endocrine therapy efficacy.Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com CME CME This material is protected by U.S.

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Farnesyl transferase inhibitors--a novel therapy for breast cancer.

Cited by 36 publications

References 30 publications

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Farnesyl transferase inhibitors: the next targeted therapies for breast cancer?

Overcoming Endocrine Therapy Resistance by Signal Transduction Inhibition

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