Biomedical Engineering Reference
In-Depth Information
ADHESION PROTEIN PHOSPHORYLATION AND
CHEMO-RESISTANCE
Cell Adhesion-Mediated Drug Resistance
It appears almost inevitable that following identii cation of a novel therapeutic
agent, shortly thereat er reports of resistance to the agent will appear in the literature.
Among the mechanisms described to mediate drug resistance, cell adhesion-
mediated drug resistance (CAM-DR) has emerged as an important contributor
(reviewed in Hehlgans
et al.
2007). h us, cancer cells deprived of attachment to
the ECM can be sensitized to the apoptosis-inducing ef ects of chemotherapeutic
agents. Conversely, integrin stimulation can cause drug resistance. h e inl uence of
integrin interaction with the ECM in promoting resistance to chemotherapeutics
and radiotherapy has been documented in a broad variety of cancer types
(reviewed in Hehlgans
et al.
2007). Importantly, elevated levels of FAK expression
and/or activity are correlated with CAM-DR, while in contrast suppression of FAK
expression can sensitize cells to drug and radiotherapy treatments.
Tamoxifen Resistance
h e anti-estrogen tamoxifen has had great success as an adjuvant therapy for treating
women with estrogen-receptor (ER)-positive breast cancer; however, up to 40% of
cancer patients receiving adjuvant tamoxifen therapy acquire resistance, whereas
50% of ER-positive tumours are intrinsically resistant to tamoxifen (Cowell
et al.
2006 and references therein). Both p130Cas and Src kinase have been implicated
as playing important roles in the resistance to tamoxifen. Elevated p130Cas
expression in primary breast tumours correlates with the failure to respond to
tamoxifen and can drive cellular proliferation in the presence of tamoxifen (van der
Flier
et al.
2000). Moreover, p130Cas, Src and FAK phosphorylation are increased
following exposure to tamoxifen
(Fig. 6)
and p130Cas phosphorylation appears to
be required for survival in the presence of tamoxifen (Cowell
et al.
2006). To date,
p130Cas phosphorylation has not been assessed in patient tumours; however, the
availability of p130Cas phospho-specii c antibodies means that this should now
be achievable.
AZD0530 inhibits Src activation in tamoxifen-resistant breast cancer cells
(Hiscox
et al.
2006), raising the possibility that anti-Src directed therapies may
be benei cial for breast cancer patients with tamoxifen-resistant disease. It is
therefore surprising that nuclear localized phosphorylated Src Y418 was positively
correlated with improved overall survival in a cohort of breast cancer patients with
known ER status biopsied prior to tamoxifen therapy (Campbell
et al.
2008). It is
dii cult to reconcile with the role for Src kinase in the development of tamoxifen
resistance with this i nding. Although active Src was detected, sequestration in the
