Therapeutic Targeting of TGF-B Signalling - Therapeutic Strategies in Cancer Biology and Pathology - page 49

collagen and integrin β1 in dermal fibroblasts derived from systemic sclerosis and in
parallel reduce the adhesive and contractile abilities of the fibroblasts (Chen et al.,
2006). Amplified expression of ALK-5 receptor gene has been encountered in neuro-
blastomas. The occurrence of somatic mutations of the kinase domain and germ line
mutations in two neuroblastoma families has led to the suggestion that the ALK gene
might be associated with the development of neuroblastomas. ShRNA (short hairpin
RNA)-mediated knockdown of the gene has resulted in the suppression of cell prolif-
eration (Janoueix-Lerosey et al., 2008).
LY2109761 is a specific receptor kinase inhibitor commonly employed in vitro and
in vivo studies into TGF-β signalling. In human HCC cell lines, inhibition of TGF-β
signalling using the TGF-β LY2109761 blocks the canonical signalling pathway and
upregulates E-cadherin mRNA and protein levels and inhibits the migration of cells
in vitro (Fransvea et al., 2008). The finding that pre-treatment of breast cancer cells
with the inhibitor enhances the radiosensitivity of the cells (Bouquet et al., 2011) aug-
ments the potential value and prospective therapeutic deployment of the TGF-β RTK
inhibitor. Type RI ALK4/5 function is inhibited by SB431542 and SB525334. These
compounds inhibit Smad phosphorylation. Ogunjimi et al. (2012) have found that
SB431542 is a selective inhibitor of ALK kinases with the exception of ALK2, which
indeed suggests that it might not inhibit signalling by BMP (bone morphogenetic pro-
tein). Further they show that Ser280-Thr mutation in RI makes it resistant to SB431542
and mutation of the corresponding Thr283-Ser in ALK2 makes it sensitive to the
inhibitor. Thus Ser280 seems to determine the selectivity for SB431542. Petersen et al.
(2008) have described another type IR kinase inhibitor GW788388 which inhibits both
type I and type IIR kinase activities. As in SB525334, no inhibition occurs of BMP
type IIR kinase. At the phenotypic level, GW788388 is able to suppress EMT. One
has to consider these findings in the context of the fact that the Src kinase inhibitors
PP1 and PP2 negate the growth inhibitory effects of TGF-β1 and also suppressed TGF-
β1 induced EMT. Tatton et al. (2003) found that PP1 can inhibit c-Kit and Bcr-Abl
RTKs. Imatinib inhibits the c-Abl kinase and suppresses the proliferative influence
of TGF-β (Wang et al., 2005). The imatinib related inhibitors dasatinib and nilotinib
effectively counteract TGF-β and PDGF signalling (Distler and Distaler, 2010). In vitro
kinase assay indicated that inhibitory effects were comparable to that of SB431542
(Ungefroren et al., 2011). So the question of selectivity of inhibition needs further
study. With Src kinase inhibitors being promiscuous in their function, perhaps there is
a case to be made for combining Src inhibitors with TGF-β receptor inhibitors.
SKI-606 (Bosutinib) seems capable of inhibiting migration of breast cancer cells
in vitro , which is accompanied by peripheral localisation of β-catenin and inhibition
of focal adhesion kinase (FAK) signalling (Vultur et al., 2008). It inhibits the phos-
phorylation of many key signalling elements, for example, Akt, MAPK besides FAK
and alters the expression of N-cadherin, fibronectin and MMPs. Also notably, SKI-
606 inhibits the expression of TGF-β and BMP in prostate cancer cells (Rabbani
et al., 2010). It is needless to say there are many such inhibitors that might be tested
for possible synergistic or additive effects. SB431542 and SB525334 have been
found to be particularly effective for increasing the cytotoxicity of Gemcitabine on