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

Unfortunately, mutant RAS has proved to be a challenging therapeutic target. After early attempts at direct targeting were unsuccessful, subsequent research with indirect targeting led to predominantly disappointing results. No drugs are currently approved that directly target RAS activity.1,3

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

Although targeting FTase initially appeared to be a logical way to stop RAS membrane binding, a major obstacle lies in enzymatic redundancy. Researchers have found that RAS prenylation can also be achieved by geranylgeranyltransferase, which means that blocking. FTase does not necessarily stop RAS membrane localization. This scenario likely explains the disappointing results of earlier FTI trials.2 Recent research, however, exploits the fact that not all RAS isoforms are so dynamic.6

The RAS family isoforms are KRAS, NRAS, and HRAS. Of these 3, HRAS exclusively relies upon FTase for prenylation, which means that FTIs are still effective in HRAS-driven cancer types.3 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

“This evidence is the first to really demonstrate that mutant HRAS is a target in cancer with FTIs,” Ho said in an interview. “The activity we’ve seen [with tipifarnib] is rapid and durable and has translated into clinical benefit in a number of different ways.”8

Treated patients had HNSCC and an HRAS mutation, with no available curative treatments. Tipifarnib was administered orally at 900 mg twice daily during alternating weeks in a 28-day cycle. Of the 4 responding patients, 2 responded for over 1 year. The patients who did not respond maintained stable disease during the trial, and tumor size decreased in all patients.

Ho said that the objective response rate of 67% (95% CI, 22%-95%) “is a remarkable response rate for a previously treated patient population.” The phase II trial was initiated in light of previous research surrounding HRAS susceptibility and anecdotal evidence that tipifarnib was effective in some patients as a single agent. Tipifarnib has been used in over 70 studies that included more than 5000 patients, and is relatively well tolerated, with less than 25% of patients discontinuing treatment due to adverse events (AEs).

Among 27 patients treated across 3 cohorts in the study, grade ≥3 treatment-emergent AEs included myelosuppression (neutropenia, 31%; anemia, 19%; and thrombocytopenia, 15%), gastrointestinal disturbances (15%), and increased creatinine (11%).

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