Biomedical Engineering Reference
In-Depth Information
17.5
Other RAF Inhibitors
Alongside PLX4032, research has led to the development of more
second generation selective BRAF inhibitors. XL281 (famotidine)
is an oral inhibitor of wild type BRAF, CRAF and mutant BRAF
V600E kinases. The phase I study of this particular drug used an
unselected patient population and showed overall prolonged disease
stabilization in two patients with BRAF V600E mutant papillary
thyroid cancer and some minor responses in nine patients with
colorectal, ovarian, and non-small-cell lung cancer. Next, a three-
arm dose expansion study including melanoma, papillary thyroid,
colorectal, and non-small-cell lung cancer patients as well as phase
I/II trials have been initiated [50, 55].
GSK 2118436 is an ATP competitive, reversible inhibitor of the
mutant BRAF V600E/K/D, wild type BRAF and CRAF kinases. A phase
I trial with over 100 patients with primarily melanoma harboring
BRAF mutations showed minimal side effects and 9% of them
developing cutaneous neoplasms, including low-grade SCC. In the
first 61 enrolled patients with metastatic disease and BRAF mutation,
85% showed tumor regression. Clinical responses were seen mainly
in lung, liver, bone, and brain metastases at the recommended phase
II dose of 150 mg twice daily [50, 56]. Subsequently, a phase II study
of GSK 2118436 and phase I study of combination drug therapy with
GSK 2118436 and a MEK-inhibitor, GSK 1220212 are in process
[50].
Taking into account the complexity of the MAPK pathway and
interplay between the signal transduction pathways in general,
combination therapies may be an effective approach [50]. Some
evidence for this includes that
melanoma models shows
the combination of BRAF/MEK inhibition increased the levels of
apoptosis [57].
At present, MEK is the only known substrate of BRAF and, thus,
MEK inhibition becomes a valuable target in affecting the entire BRAF
pathway [22]. Preclinical studies using small molecule MEK 1/2
inhibitors reduced proliferation of various cancer cell lines through
apoptosis and cell-cycle arrest [58]. The first small-molecule MEK
inhibitor CL1040 showed favorable phase I trial results but drug
development was later curbed given its poor pharmacodynamics in
phase II trials [59, 60]. Another second-generation MEK inhibitor
PD0325901 exhibited greater activity than the first-generation MEK
in vitro
