Farnesyltransferase inhibitors: potential therapeutic for inflammatory breast cancer?
Inflammatory breast cancer (IBC) is an aggressive and poorly managed disease that accounts for up to 6% of new breast cancer cases in the United States annually. Recent preclinical findings suggest that IBC might be treated with farnesyltransferase inhibitors (FTIs), a novel class of experimental therapeutics that are currently in clinical trials. FTIs exhibit considerable selectivity and efficacy against tumors in preclinical models, and they have been well-tolerated in Phase I human trials. How FTIs target cancer cells has emerged as an important question, with the somewhat disappointing results from initial Phase II efficacy trials. FTI development was predicated on Ras inhibition but there is considerable evidence that other mechanisms are important for mediating the antineoplastic activities of these drugs. One important mediator that has emerged is RhoB, a small GTPase that is recruited by FTIs to trigger growth inhibition and apoptosis. Recently, van Golen and Merajver and their colleagues have demonstrated that FTIs will recruit RhoB to suppress IBC cell phenotypes or neoplastic transformation of human mammary epithelial cells by RhoC, a key oncogenic driver in IBC. A mechanistic implication of this study is that RhoB can interfere with RhoC-dependent signals required for neoplastic pathophysiology. Further preclinical and clinical investigations to test the potential therapeutic utility of FTIs for treating RhoC-driven breast cancers such as IBC would seem warranted.
Prendergast
George C
GC
Lankenau Institute for Medical Research, Wynnewood PA 19096, USA. prendergastg@mlhs.org