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<p>Inflammatory breast cancer (IBC) is a rare and highly aggressive form of breast
cancer that is characterized by survival signaling through overexpression and/or activation
of the epidermal growth factor receptors EGFR/ErbB1 and Her2/ErbB2 and defects in
the apoptotic program. The development of therapeutic resistance is a significant
barrier to successful treatment in IBC, and thus, strategies targeting the mechanisms
that drive drug resistance could prevent or reverse therapeutic resistance, significantly
improving patient prognosis. Based on analysis of previously developed models of therapeutic
resistant IBC, we hypothesized that apoptotic dysregulation and redox adaptive mechanisms
were central to the drug resistant phenotype in IBC cells, and that targeting of these
mechanisms could overcome therapeutic resistance. Our objectives to address this hypothesis
were: 1. to develop and characterize an isotype-matched IBC cellular model to investigate
the mechanisms of acquired therapeutic resistance; 2. to characterize IAP-specific
small molecule inhibitors as a means of targeting the mechanism of apoptotic dysregulation
in IBC; and 3. to characterize a novel redox modulatory combination as a means of
targeting redox adaptive mechanisms in IBC.</p><p>Analysis of cell viability, proliferation,
and growth parameters, evaluation of protein expression and signaling via western
immunoblot, and measurement of reactive oxygen species (ROS), antioxidants, and apoptosis
in patient-derived IBC cell lines and isogenic derivatives revealed that resistance
to the ErbB1/2 inhibitor lapatinib was protective against other targeted agents and
chemotherapeutics. Additionally, reversal of resistance was associated with enhanced
ability to accumulate ROS and downregulation of anti-apoptotic and antioxidant proteins.
Targeting of resistance mechanisms using small molecule IAP inhibitors and a redox
modulatory strategy both effectively induced apoptosis in therapy resistant IBC cells.
Together, these results confirm XIAP and the redox adaptive phenotype as promising
therapeutic targets for IBC and demonstrate the feasibility of targeting those mechanisms
in order to reverse therapeutic resistance.</p>
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