| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1930831 | Biochemical and Biophysical Research Communications | 2011 | 8 Pages |
Primary resistance of HER2 gene-amplified breast carcinomas (BC) to HER-targeted therapies can be explained in terms of overactive HER2-independent downstream pro-survival pathways. We here confirm that constitutive overexpression of Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2-positive BC cells with intrinsic cross-resistance to multiple HER1/2 inhibitors. The IC50 values for the HER1/2 Tyrosine Kinase Inhibitors (TKIs) gefitinib, erlotinib and lapatinib were up to 40-fold higher in trastuzumab-unresponsive JIMT-1 cells than in trastuzumab-naïve SKBR3 cells. ELISA-based and immunoblotting assays demonstrated that trastuzumab-refractory JIMT-1 cells constitutively expressed ∼4 times more survivin protein than trastuzumab-responsive SKBR3 cells. In response to trastuzumab, JIMT-1 cells accumulated ∼10 times more survivin than SKBR3 cells. HER1/2 TKIs failed to down-regulate survivin expression in JIMT-1 cells whereas equimolar doses of HER1/HER2 TKIs drastically depleted survivin protein in SKBR3 cells. ELISA-based detection of histone-associated DNA fragments confirmed that trastuzumab-refractory JIMT-1 cells were intrinsically protected against the apoptotic effects of HER1/2 TKIs. Of note, when we knocked-down survivin expression using siRNA and then added trastuzumab, cell proliferation and colony formation were completely suppressed in JIMT-1 cells. Our current findings may be extremely helpful to design successful combinatorial strategies aimed to circumvent the occurrence of de novo resistance to HER2-directed drugs using survivin antagonists.
► Intrinsic trastuzumab resistance occurs in ∼70% of metastatic HER2 + breast carcinomas (BC). ► Approximately 15% of early HER2 + BC relapse in spite of treatment with trastuzumab-based therapies. ► HER2-independent downstream pro-survival pathways might underlie trastuzumab refractoriness. ► Survivin is indispensable for proliferation and survival of HER2 + BC unresponsive to HER2-targeted therapies ab initio. ► Survivin antagonists may clinically circumvent the occurrence of de novo resistance to HER2-directed drugs.
