Inhibiting Ras Signaling in the Therapy of Breast Cancer

Abstract

Ras is a small guanosine triphosphate—binding protein that plays an important role in signal transduction pathways that influence cellular proliferation, apoptosis, cytoskeletal organization, and other important biological processes. Prenylation of Ras proteins by the enzyme farnesyltransferase renders the protein hydrophobic, causing localization to the inner surface of the cell membrane, where it exerts its biological effects. Ras mutations that result in constitutive activation of the Ras pathway are common in certain human cancers, and transfection of cell lines with mutant Ras renders them tumorigenic. Farnesyltransferase inhibitors (FTIs) were initially developed to inhibit growth of cancers harboring Ras mutations, but preclinical data suggests that they also have antiproliferative effects in cell lines with wild-type Ras. Preclinical data suggest that FTIs have antiproliferative and antitumor effects in breast cancer cell lines, but the precise target(s) remain to be defined. One phase II trial has demonstrated that one orally administered FTI has significant antitumor activity in metastatic breast cancer. In addition, preclinical evidence suggests that FTIs may augment the activity of cytotoxic agents and hormonal therapy. Clinical trials are currently underway evaluating whether these agents have a useful role in the management of advanced breast cancer.