Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Clinical Applications of Pharmacogenomics in Cancer Therapy
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intolerant to prior tyrosine kinase therapy. Ponatinib inhibits tyrosine kinase activity
of ABL and T315I mutant. Ponatinib offers advantages compared to other TKIs
as it has activity of T315I mutant. 109
BRAF AND MEK INHIBITION IN MELANOMA
WITH BRAF V600 MUTATIONS
Metastatic melanoma is one of the most difficult advanced malignancies to treat.
Most of the standard chemotherapy, radiotherapy, and even biological therapies,
such as interleukin and interferon, have failed to significantly improve the OS
for patients with advanced melanoma. One of the breakthroughs in the treatment
of advanced melanoma is to block MAPK signaling targeting at BRAF V600E
mutations. Until recently, there were no targeted therapies for BRAF mutations for
advanced melanoma. Three therapies have emerged in recent years: vemurafenib
(Zelboraf ® ), dabrafenib (Tafinlar ® ), and trametinib (Mekinist ® ). The MAPK pathway
plays an important role in stimulating the growth of melanoma cells by activating
the downstream RAF kinase that causes phosphorylation of the MEK kinases.
Activated MEK kinases phosphorylate the ERK kinases and regulate cyclin D1
expression, leading to tumor cell proliferation. Certain BRAF serine–threonine
kinase mutations lead to constitutive activation of BRAF protein in metastatic melanoma
in the absence of growth factors, which activates the cascade of the RAS–
RAF–MEK–ERK signaling pathway and significantly contributes to the growth
and progress of melanoma tumors. BRAF V600E mutation is the most common
mutation in melanoma and accounts for about 80% of all BRAF mutations. Other
BRAF mutations include V600K, V600D/V600R, and G469A, which account for
about 16%, 3%, and 1% of BRAF mutations, respectively.
Vemurafenib is the first drug in its class that is a BRAF inhibitor of the activated
BRAF V600E gene. Vemurafenib is indicated for the treatment of unresectable or
metastatic melanoma with BRAF V600E as detected by an FDA-approved test.
Vemurafenib inhibits tumor growth by inhibiting kinase activities of BRAF and
other kinases such as CRAF, ARAF, and FGR. Vemurafenib has antitumor effects in
cellular and animal models of melanomas with mutated BRAF V600E and has been
associated with prolonged OS and PFS. In a phase III study of vemurafenib vs. dacarbazine,
the PFS and ORR were improved with vemurafenib. 110 However, after about
seven months of treatment with vemurafenib, melanoma tumors acquire resistance to
vemurafenib by bypassing BRAF signaling through stimulating other downstream
or producing BRAF transcriptional splice variants.
Dabrafenib is an inhibitor of some mutated forms of BRAF kinases, as well as
wild-type BRAF and CRAF kinases. Some mutations in the BRAF gene, including
those that result in BRAF V600E, can result in constitutively activated BRAF
kinases that may stimulate tumor cell growth. Dabrafenib is specifically indicated
for the treatment of patients with unresectable or metastatic melanoma with BRAF
V600E mutation. Dabrafenib is not indicated for the treatment of patients with wildtype
BRAF melanoma. 67 In a phase III trial, dabrafenib was compared to dacarbazine,
and the results shows that dabrafenib significantly increase PFS compared
with dacarbazine. 111 Dabrafenib is also used in combination with trametinib for the