Chronic activation of
Ras proteins by mutational activation or by
growth factor stimulation is a common occurrence in many human
cancers and was shown to induce and be required for
tumor growth. Even if additional genetic defects are present, "correction" of the Ras defect has been shown to reverse Ras-dependent
tumorigenesis. One way to block
Ras protein activity is by interfering with their spatiotemporal localization in cellular membranes or in membrane microdomains, a prerequisite for Ras signaling and
biological activity. Detailed reports describe the use of this method in studies employing
farnesylthiosalicylic acid (FTS,
Salirasib), a Ras farnesylcysteine mimetic, which selectively disrupts the association of chronically active
Ras proteins with the plasma membrane. FTS competes with Ras for binding to Ras-escort
proteins, which possess putative farnesyl-binding domains and interact only with the activated form of
Ras proteins, thereby promoting Ras nanoclusterization in the plasma membrane and robust signals. This chapter presents three-dimensional time-lapse images that track the FTS-induced inhibition of membrane-activated Ras in live cells on a real-time scale. It also describes a mechanistic model that explains FTS selectivity toward activated Ras. Selective blocking of activated
Ras proteins results in the inhibition of Ras transformation in vitro and in animal models, with no accompanying toxicity. Phase I clinical trials have demonstrated a safe profile for oral FTS, with minimal side effects and promising activity in
hematological malignancies.
Salirasib is currently undergoing trials in patients with
pancreatic cancer and with
nonsmall cell lung cancer, with or without identified K-Ras mutations. The findings might indicate whether with the disruption of the spatiotemporal localization of oncogenic
Ras proteins and the targeting of
prenyl-binding domains by anticancer drugs is worth developing as a means of
cancer treatment.