Biomedical Engineering Reference
In-Depth Information
2005). TAE226 also showed ei cacy against a range of cultured breast cancer
cell lines (Golubovskaya
et al.
2008). Similarly, PF-562,271 stimulated increased
apoptosis and decreased vascularization in multiple mouse tumour models of
human sub-cutaneous xenograt s (Roberts
et al.
2008).
PHOSPHORYLATION OF ADHESION PROTEINS AS
POTENTIAL BIOMARKERS
Phosphorylation Response to Anti-FAK and Anti-Src
Therapeutics
Phospho-specii c antibodies to FAK pY
397
and Src pY
418
are proving to be excellent
markers for the ei cacy of therapies targeting FAK and Src, respectively. Indeed, a
number of studies coni rm loss of FAK and Src phosphorylation in a range of cancers
following application of anti-FAK and anti-Src drugs
(Table 1)
. h e report that Src
phosphorylation was reduced following dasitinib treatment in dasatinib-sensitive
but not -resistant cell lines (Eustace
et al.
2008) suggests that Src phosphorylation
status may serve as a biomarker to potentially discriminate responsive from non-
responsive tumours. One study suggested Src phosphorylation status prior to
therapy did not predict response to Src inhibitors (Johnson
et al.
2005); however,
the potential for Src phosphorylation status as a predictor of therapeutic response
warrants further investigation with large patient cohorts of dif erent tumour
types.
Table 1
Studies of FAK and Src phosphorylation following anti-FAK and anti-Src
treatments
Chemotherapeutic
Phospho-target
Tumour type
References
TAE226
FAK Y397
neuroblastoma
(Beierle
et al
. 2008)
breast
(Golubovskaya
et al
. 2008)
ovarian
(Halder
et al
. 2005)
glioma
(Shi
et al
. 2007)
PF-562,271
FAK Y397
glioblastoma*
(Roberts
et al
. 2008)
Dasatinib
Src Y418
melanoma
(Eustace
et al
. 2008)
head and neck
(Johnson
et al
. 2005)
prostate*
(Luo
et al
. 2008)
colon*
(Serrels
et al.
2006)
*
In vivo
cancer models. h e table shows the anti-FAK and anti-Src therapies that have been demonstrated to
specii cally reduce phosphorylation of their target protein (phospho-target) in the indicated tumour cell types.
Phosphorylation of paxillin, FAK and p130Cas has also been used to monitor
Src kinase inhibition. A number of studies report reduced phosphorylation of the
Src phosphorylation target sites in FAK, while FAK pY
397
is maintained (Johnson
