Overcoming chemoresistance of small-cell lung cancer through stepwise HER2-targeted antibody-dependent cell-mediated cytotoxicity and VEGF-targeted antiangiogenesis

Abstract

Small-cell lung cancer (SCLC) easily recurs with a multidrug resistant phenotype. However, standard therapeutic strategies for relapsed SCLC remain unestablished. We found that human epidermal growth factor receptor 2 (HER2) is not only expressed in pretreated human SCLC specimens, but is also upregulated when HER2-positive SCLC cells acquire chemoresistance. Trastuzumab induced differential levels of antibody-dependent cell-mediated cytotoxicity (ADCC) to HER2-positive SCLC cells. Furthermore, as a mechanism of the differential levels of ADCC, we have revealed that coexpression of intracellular adhesion molecule (ICAM)-1 on SCLC cells is essential to facilitate and accelerate the trastuzumab-mediated ADCC. Although SN-38–resistant SCLC cells lacking ICAM-1 expression were still refractory to trastuzumab, their in vivo growth was significantly suppressed by bevacizumab treatment due to dependence on their distinctive and abundant production of vascular endothelial growth factor. Collectively, stepwise treatment with trastuzumab and bevacizumab is promising for the treatment of chemoresistant SCLC.

ATM kinase sustains HER2 tumorigenicity in breast cancer

“…The induction of AKT phosphorylation has been clearly linked to sustained cell proliferation and tumorigenicity; specific compounds, including Trastuzumab and Lapatinib, which target the kinase activity of HER2 and EGF receptor, may interfere with this signalling [33][34][35] . We therefore set out to investigate whether ATM inhibition might also result in the modulation of AKT phosphorylation.…”

“…However, a major problem is that the lack of comprehension of the molecular mechanisms promoting resistance or acquired resistance, significantly reduces this treatment's success rate. Sensitivity is strictly dependent on HER2 high expression and has been mainly linked to an inhibitory effect of Trastuzumab on cell proliferation [33][34][35] . Accordingly we show that HER2-overexpressing cells where ATM has been downregulated by specific shRNA interference became significantly resistant to Trastuzumab; this further supports the conclusion that ATM sustains HER2 expression, required for efficient targeting (Fig.…”

Chemotherapy-Regulated microRNA-125–HER2 Pathway as a Novel Therapeutic Target for Trastuzumab-Mediated Cellular Cytotoxicity in Small Cell Lung Cancer

“…Several previous reports have shown that the percentage of HER2-positive SCLC clinical sample is approximately 30%, which compares favorably with the percentage of HER2-positive breast or gastric cancers. Because anti-HER2 treatment is a useful therapy for these other cancers, expression of HER2 in SCLC cells suggests the possibility that HER2 may also be a promising therapeutic target for SCLC (24,25). Previously, Minami and colleagues (25) found six HER2-positive SCLC cell lines among 13 SCLC cell lines, including SBC-3 and SBC-5, and that all of these HER2-positive cell lines were derived from Japanese SCLC patients, indicating the ethnic differences of HER2 expression.…”

Missing the Target?—Targeted Therapy in Small Cell Lung Cancer

“…• Human epidermal growth factor receptor 2 [HER2]-Pre-clinical studies suggest HER2 is up regulated in chemoresistant SCLC and recent research suggests trastuzumab could inhibit this effect via antibody-dependent cell-mediated toxicity [46]. This is yet to reach in vivo studies.…”