Biomedical Engineering Reference
In-Depth Information
BRAF mutation was present. Then, high nanomolar concentrations
of the drug could essentially block the V600E BRAF mutated cells
from proliferating
[4]. Importantly, PLX4032 only inhibits
RAF in cells with the BRAF V600E mutation [48]. Normally, RAF
proteins form dimers and binding of a drug to one RAF in the dimer
can subsequently activate the other given that there is normal RAS
activity [48]. Yet, in these mutant BRAF cells, there is insufficient RAS
activation to create RAF dimers, which allows for BRAF inhibiting
drugs to abrogate RAF activity and ERK signaling pathway [48].
Thus, identifying the mutation status of the cancer prior to initiating
any BRAF-targeted therapy is integral in treatment options.
As an aside, PLX4032 was initially formulated as a crystalline
preparation. However, due to poor bioavailability, a new micro
precipitated bulk powder form was made available [4]. Recently,
Flaherty
in vitro
reported the results of the phase I trial of PLX4032.
In the phase II dose-escalation trial, 49 of the 55 patients enrolled
with solid tumors had melanoma, and it was determined that the
recommended phase II drug dose, defined as the highest dose at
which no more than 1 of 6 patients had dose-limiting side effects, to
be 960 mg twice daily [4]. Of note, out of 16 of those patients with
melanoma in the dose-escalation group who specifically carried
the V600E BRAF mutation and had received 240 mg or more of
PLX4032 twice daily, 10 had partial responses and 1 with a complete
response [4]. The tumor response occurred early in the treatment
course. The median response duration was 9 months, and among
the patients receiving the phase II dose, the median progression-
free survival period was more than 7 months, placing encouraging
implications on the natural course of the disease [49]. The most
common dose-limiting side effects included arthralgia, nausea, skin
rash, photosensitivity, fatigue, cutaneous squamous-cell carcinoma,
pruritus, and palmar-plantar dysesthesia [4].
Most concerning side effect was the development of the
cutaneous neoplasms, which is thought to be an upstream activation
of the RAS mutations in pre-existing skin lesions [50]. Alterations
in the dimerization of the BRAF kinase by selective BRAF inhibitors
can lead to paradoxical activation of the MAPK pathway in the
squamous cells [48, 51, 52]. Specifically, in the discussed phase I
and II trials, 38% of the 48 patients with melanoma who received
the highest doses of drug developed well-differentiated squamous
et al.
