Here, we showed a significant induction of apoptotic cell death following AZD8931 treatment in vitro in IBC cells. Most significantly, in current IBC models, we showed that AZD8931 monotherapy significantly inhibited tumor growth and the combination of paclitaxel + AZD8931 resulted in the highest levels of tumor growth inhibition in vivo in both cell lines (Figure 4). The most common treatment for IBC is multimodal involving neoadjuvant
combination chemotherapy followed by surgery, selleck adjuvant chemotherapy, or radiotherapy [5]. Conventional chemotherapy regimens are not sufficient for the treatment of IBC, particularly for TNIBC. Targeted therapy against HER2 is one promising strategy for the treatment of IBC patients with HER2 amplification. Several EGFR targeted therapies including small molecule inhibitors and anti-EGFR antibodies have been evaluated in preclinical and clinical studies [21–25]. Patients with EGFR expressing tumors did not respond to EGFR-targeted therapy, which suggests that EGFR expression alone does not indicate tumor cell growth https://www.selleckchem.com/products/Staurosporine.html dependence on the EGFR pathway.
One study indicated that the significant interactions between EGFR and other alternative signaling pathway kinases, such as c-MET and IGF-1R are linked to resistance to targeted therapies [26]. Thus, future studies are warranted to consider combining of EGFR-targeted therapy with drugs targeting other alternate signaling pathways to improve efficacy. Several antibodies targeting EGFR have also been investigated for their efficacy in patients with TNBC, some results have showed the clinical benefit in combination BIBW2992 purchase with chemotherapy drugs for patients with TNBC [27, 28]. Metastasis is the primary cause of breast cancer mortality. IBC is characterized by locally advanced disease and high rates of metastasis even after multimodality treatments [29]. In IBC, inflammation is associated with the invasion of aggregates of tumor
cells defined as tumor emboli, into the dermal lymphatics causing an obstruction of the lymph Phosphatidylinositol diacylglycerol-lyase channels [30]. Currently, the molecular pathways driving the early development of metastasis in IBC remain poorly characterized. EGFR family and its downstream signaling pathways are known to promote cell migration, angiogenesis, invasion, and metastasis [22]. Previous studies have shown that the EGFR inhibitor erlotinib (Tarceva™) significantly inhibited cell motility, invasiveness, tumor growth, and spontaneous lung metastasis in EGFR-expressing IBC models [31]. Further therapeutic studies are warranted to examine the effects of AZD8931 on the invasiveness and metastasis of IBC. Conclusions We demonstrate that EGFR/HER2/HER3-targeting with AZD8931 is associated with promising preclinical activity in EGFR-overexpressed and HER2 non-amplified IBC models, suggesting an important novel therapeutic approach for this aggressive disease.