EGFR Signalling in EMT - Therapeutic Strategies in Cancer Biology and Pathology - page 52

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EGFR Signalling in EMT

The EGFR family have been known for a while to be actively related to activation of
EMT and the acquisition of biological features associated with cellular transforma-
tion to the EMT phenotype and drug resistance. EGF is a proven promoter of cell
proliferation and is known to induce EMT. It decreases cell adhesion and enhances
cell motility. Investigations into EGFR family in relation to EMT have acquired
much impetus due to the problem of drug resistance encountered in patient manage-
ment. The mechanisms of acquired resistance to Trastuzumab in patients expressing
HER2 at high levels are being seriously addressed at present. It has been suggested
that upregulation of EGFR might be one of the mechanism involved in the induction
of the EMT phenotype and this acquired resistance ( Figure 8.1 ).

E-cadherin in EGFR Signalling

The induction of the EMT phenotype by EGFR activation may occur by several routes.
The involvement of E-cadherin with its expression being suppressed in EGFR-mediated
induction of EMT is now a distinct possibility, indeed recognised many years ago. Jones
et al. (1996) reported that the loss of E-cadherin markedly correlated with levels of EGFR
expression. Activation of EGFR and transactivation of HER2 initiates signalling cascades
that lead to increased motility and invasion. EGF treatment and EGFR activation have the
effects of downregulating E-cadherin expression, whereas inhibition of EGFR enhances
E-cadherin expression (Zhang et al., 2012f; Cheng et al., 2012a). On the other hand,
EMT and the expression of EMT markers are suppressed when EGFR activity is inhib-
ited. Also E-cadherin expression is upregulated with attendant reduction in the Snail and
Slug transcription factors that are negative regulators of E-cadherin expression (Chang
et al., 2012b). Similarly serous borderline ovarian tumours EGF treatment upregulated
Snail, Slug and ZEB1 leading to the suppression of E-cadherin and induction of EMT.
EGFR kinase inhibitors geftinib and erlotinib constitute effective treatment of lung
cancers where activating mutation of EGFR are present (Engelman et al., 2007). Using
geftinib-sensitive PC9 cells and a resistant clone (PC9/gef), Chang et al. (2011d) were
able to demonstrate an enhanced expression of Slug in the resistant PC9 cells as com-
pared with the sensitive ones. However, the mechanism involved in acquired geftinib
resistance can involve secondary EGFR mutation as well as overexpression of HGF
and amplification of its receptor c-met (Engelman et al., 2007; Kosaka et al., 2011).
HGF-mediated induction of cell invasion and EMT does indeed involve upregulation
of Snail. This seems to occur via the MAPK/Egr (early growth response)-1 pathway
which leads to Snail upregulation and repression of E-cadherin (Grotegut et al., 2006).