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In eukaryotes, double-stranded (ds) RNA induces sequence-specific inhibition of gene expression referred to as RNA interference (RNAi). We exploited RNAi to define the role of HER2/neu in the neoplastic proliferation of human breast cancer cells. We transfected SK-BR-3, BT-474, MCF-7, and MDA-MB-468 breast cancer cells with short interfering RNA (siRNA) targeted against human HER2/neu and analyzed the specific inhibition of HER2/neu expression by Northern and Western blots. Transfection with HER2/neu-specific siRNA resulted in a sequence-specific decrease in HER2/neu mRNA and protein levels. Moreover, transfection with HER2/neu siRNA caused cell cycle arrest at G0/G1 in the breast cancer cell lines SKBR-3 and BT-474, consistent with a powerful RNA silencing effect. siRNA treatment resulted in an antiproliferative and apoptotic response in cells overexpressing HER2/neu, but had no influence in cells with almost no expression of HER2/neu proteins like MDA-MB-468 cells. These data indicate that HER2/neu function is essential for the proliferation of HER2/neuoverexpressing breast cancer cells. Our observations suggest that siRNA targeted against human HER2/neu may be valuable tools as anti proliferative agents that display activity against neoplastic cells at very low doses.
The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS.
This study presents comprehensive real-world data on the use of anti-human epidermal growth factor receptor 2 (HER2) therapies in patients with HER2-positive metastatic breast cancer (MBC). Specifically, it describes therapy patterns with trastuzumab (H), pertuzumab + trastuzumab (PH), lapatinib (L), and trastuzumab emtansine (T-DM1). The PRAEGNANT study is a real-time, real-world registry for MBC patients. All therapy lines are documented. This analysis describes the utilization of anti-HER2 therapies as well as therapy sequences. Among 1936 patients in PRAEGNANT, 451 were HER2-positive (23.3%). In the analysis set (417 patients), 53% of whom were included in PRAEGNANT in the first-line setting, 241 were treated with H, 237 with PH, 85 with L, and 125 with T-DM1 during the course of their therapies. The sequence PH → T-DM1 was administered in 51 patients. Higher Eastern Cooperative Oncology Group (ECOG) scores, negative hormone receptor status, and visceral or brain metastases were associated with more frequent use of this therapy sequence. Most patients received T-DM1 after treatment with pertuzumab. Both novel therapies (PH and T-DM1) are utilized in a high proportion of HER2-positive breast cancer patients. As most patients receive T-DM1 after PH, real-world data may help to clarify whether the efficacy of this sequence is similar to that in the approval study.