while patients under dacarbazine (as a control) showed only a survival of 9.9 months.
Furthermore, vemurafenib resulted in a significant response in 48.4% of patients
(in comparison with 5.5% in the dacarbazine-treated group) [113, 114].
Although vemurafenib was in general well tolerated by patients, several adverse
symptoms were found upon treatment such as fatigue, nausea, alopecia,
lymphopenia, neutropenia, headache, and diarrhea [113, 115–118].
Dabrafenib was shown to be in general a more potent Raf inhibitor than
vemurafenib. It inhibits BRAF
V600E with an IC 50 of 0.8 nM, wild-type BRAF with
an IC 50 of 3.2 nM, and RAF1 with an IC 50 of 5 nM [109, 119]. In preclinical assays,
dabrafenib also showed efficacy against BRAF-mutated cell lines and reduced tumor
development in xenograft melanoma mouse models [119]. A phase-III clinical trial
of dabrafenib was performed in a total of 250 patients suffering from BRAF
V600E -
mutated metastatic melanoma. While 187 patients received 150 mg dabrafenib twice
per day, 63 patients received dacarbazine treatment [120]. In the dabrafenib-treated
group, 6 patients (3%) showed a complete and 87 patients (47%) partial response,
while 78 patients (42%) displayed a stable disease. In the dacarbazine group, one
patient (2%) showed a complete and three patients (5%) partial response. A stable
disease was seen in 30 patients (48%). The median progression-free survival in the
dabrafenib group was 5.1 months, while dacarbazine-treated patients showed a
progression-free survival rate of 2.7 months.
Side effects found often associated with dabrafenib treatment were pyrexia,
headache, neutropenia, fatigue, thrombocytopenia, leukopenia, asthenia,
hyponatremia, arthralgia, nausea, chills, myalgia, vomiting, diarrhea, and hair loss
[108, 109, 117, 118, 120].
Overall, vemurafenib and dabrafenib induced initial therapeutic effects against
BRAF
V600 mutant melanomas. However, the long-term treatment success is limited
due to the development of secondary resistance. Thus, most patients relapse after
1 year of treatment [121]. In addition, other tumor entities with BRAF
V600E mutation, such as colorectal, pancreatic, and thyroid cancer, mostly show a primary
resistance to these drugs [122, 123]. It was hypothesized that long-term control of
tumor development by these inhibitors is limited by the fact that they do not
efficiently inhibit the dimerization of RAF and are partly unsuccessful in targeting
BRAF and RAF1 dimers. Thus, BRAF homodimeric or BRAF-RAF1 heterodimeric
signaling can trigger therapy resistance [100–102]. In addition, it was shown that
therapy resistance of RAF inhibition can be also induced by the formation of
different BRAF
V600E splice variants which can form resistant dimers [124].
Of note, RAF inhibitors were also applied in tumors without BRAF mutation. For
example, the previously mentioned multikinase inhibitor sorafenib represents a RAF
inhibitor and showed certain efficacy in the treatment of patients with HCC and
RCC. Sorafenib was approved by the FDA for the treatment of these tumor types
[125–129]. However, development of resistance against sorafenib is a frequent
incident in treated patients.
Sorafenib inhibits RAF1 with an IC 50 of 6 nM, wild-type BRAF with an IC 50 of
25 nM, and BRAF
V600E with an IC 50 of 38 nM. Of note, it is hypothesized that the
effect of sorafenib is based on a combined inhibition of RAF and other kinases such
Exploiting Kinase Inhibitors for Cancer Treatment: An Overview of Clinical. . .
139
Furthermore, vemurafenib resulted in a significant response in 48.4% of patients
(in comparison with 5.5% in the dacarbazine-treated group) [113, 114].
Although vemurafenib was in general well tolerated by patients, several adverse
symptoms were found upon treatment such as fatigue, nausea, alopecia,
lymphopenia, neutropenia, headache, and diarrhea [113, 115–118].
Dabrafenib was shown to be in general a more potent Raf inhibitor than
vemurafenib. It inhibits BRAF
V600E with an IC 50 of 0.8 nM, wild-type BRAF with
an IC 50 of 3.2 nM, and RAF1 with an IC 50 of 5 nM [109, 119]. In preclinical assays,
dabrafenib also showed efficacy against BRAF-mutated cell lines and reduced tumor
development in xenograft melanoma mouse models [119]. A phase-III clinical trial
of dabrafenib was performed in a total of 250 patients suffering from BRAF
V600E -
mutated metastatic melanoma. While 187 patients received 150 mg dabrafenib twice
per day, 63 patients received dacarbazine treatment [120]. In the dabrafenib-treated
group, 6 patients (3%) showed a complete and 87 patients (47%) partial response,
while 78 patients (42%) displayed a stable disease. In the dacarbazine group, one
patient (2%) showed a complete and three patients (5%) partial response. A stable
disease was seen in 30 patients (48%). The median progression-free survival in the
dabrafenib group was 5.1 months, while dacarbazine-treated patients showed a
progression-free survival rate of 2.7 months.
Side effects found often associated with dabrafenib treatment were pyrexia,
headache, neutropenia, fatigue, thrombocytopenia, leukopenia, asthenia,
hyponatremia, arthralgia, nausea, chills, myalgia, vomiting, diarrhea, and hair loss
[108, 109, 117, 118, 120].
Overall, vemurafenib and dabrafenib induced initial therapeutic effects against
BRAF
V600 mutant melanomas. However, the long-term treatment success is limited
due to the development of secondary resistance. Thus, most patients relapse after
1 year of treatment [121]. In addition, other tumor entities with BRAF
V600E mutation, such as colorectal, pancreatic, and thyroid cancer, mostly show a primary
resistance to these drugs [122, 123]. It was hypothesized that long-term control of
tumor development by these inhibitors is limited by the fact that they do not
efficiently inhibit the dimerization of RAF and are partly unsuccessful in targeting
BRAF and RAF1 dimers. Thus, BRAF homodimeric or BRAF-RAF1 heterodimeric
signaling can trigger therapy resistance [100–102]. In addition, it was shown that
therapy resistance of RAF inhibition can be also induced by the formation of
different BRAF
V600E splice variants which can form resistant dimers [124].
Of note, RAF inhibitors were also applied in tumors without BRAF mutation. For
example, the previously mentioned multikinase inhibitor sorafenib represents a RAF
inhibitor and showed certain efficacy in the treatment of patients with HCC and
RCC. Sorafenib was approved by the FDA for the treatment of these tumor types
[125–129]. However, development of resistance against sorafenib is a frequent
incident in treated patients.
Sorafenib inhibits RAF1 with an IC 50 of 6 nM, wild-type BRAF with an IC 50 of
25 nM, and BRAF
V600E with an IC 50 of 38 nM. Of note, it is hypothesized that the
effect of sorafenib is based on a combined inhibition of RAF and other kinases such
Exploiting Kinase Inhibitors for Cancer Treatment: An Overview of Clinical. . .
139