FTase Inhibition Holds Promise for RAS Targeting and Beyond

William Pass, DVM
Published: Tuesday, May 15, 2018
Alan L. Ho, MD, PhD

Alan L. Ho, MD, PhD
For more than 20 years, researchers have known that the RAS pathway is involved in a wide variety of cancer types. RAS proteins normally switch between an active state, which is bound by guanosine triphosphate, and an inactive state, which is bound by guanosine diphosphate, to regulate cell-cycle progression. In cancer, the mutant RAS gene becomes locked in the active state, causing uncontrolled cell proliferation.1 Such mutations are found in 30% of all neoplasms, with a higher prevalence in colon cancer (~50%) and pancreatic cancer (~90%).2

Despite this rocky terrain, recent success with tipifarnib, a biologically active drug known as a farnesyltransferase inhibitor (FTI), brings promise for treating solid tumors and hematological malignancies. In time, FTIs may be utilized in a variety of cancer types and other diseases as associated pathways become better defined.


Farnesyltransferase (FTase) is an enzyme that plays a key role in RAS posttranslational processing (Figure).1,4 Specifically, FTase is responsible for farnesylation, a type of prenylation, in which a hydrophobic group is added to the C-terminal CAAX motif of a RAS protein. Prenylation allows for RAS membrane binding and subsequent downstream signaling; without it, mutant RAS becomes inert, thereby halting uncontrolled cell proliferation.5

Ongoing research into this subclass of RAS proteins is yielding promising results.

Figure. FTI Inhibition and RAS Signaling


Tipifarnib Effective for HRAS-Mutant HNSCC

A study by Alan L. Ho, MD, PhD, a medical oncologist and the Geoffrey Beene Junior Faculty Chair at Memorial Sloan Kettering Cancer Center, is investigating the efficacy of tipifarnib, a first-in-class, highly selective FTI that competitively binds to the CAAX motif of FTase. Treatment with tipifarnib has produced partial responses in 4 of 6 patients with HRAS-mutant head and neck squamous cell carcinoma (HNSCC).7
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