Gene amplification drives oncogenesis in a broad spectrum of cancers. A number of drugs have been developed to inhibit the protein products of amplified driver genes, but their clinical efficacy is often hampered by drug resistance. Here, we introduce a therapeutic strategy for targeting cancer-associated gene amplifications by activating the DNA damage response with triplex-forming oligonucleotides (TFOs), which drive the induction of apoptosis in tumors, whereas cells without amplifications process lower levels of DNA damage. Focusing on cancers driven by HER2 amplification, we find that TFOs targeting HER2 induce copy number-dependent DNA double-strand breaks (DSBs) and activate p53-independent apoptosis in HER2-positive cancer cells and human tumor xenografts via a mechanism that is independent of HER2 cellular function. This strategy has demonstrated in vivo efficacy comparable to that of current precision medicines and provided a feasible alternative to combat drug resistance in HER2-positive breast and ovarian cancer models. These findings offer a general strategy for targeting tumors with amplified genomic loci.

基因扩增在广泛的癌症中驱动肿瘤发生。已经开发了许多药物来抑制扩增驱动基因的蛋白质产物，但它们的临床疗效往往受到耐药性的阻碍。在这里，我们介绍了一种靶向癌症相关基因扩增的治疗策略，通过用形成三链体的寡核苷酸 (TFO) 激活 DNA 损伤反应，驱动肿瘤细胞凋亡，而没有扩增的细胞处理较低水平的 DNA 损伤。专注于由HER2扩增驱动的癌症，我们发现靶向HER2的 TFO通过不依赖于 HER2 细胞功能的机制，在 HER2 阳性癌细胞和人类肿瘤异种移植物中诱导拷贝数依赖性 DNA 双链断裂 (DSB) 并激活 p53 非依赖性细胞凋亡。该策略已经证明了与当前精准药物相当的体内疗效，并为对抗 HER2 阳性乳腺癌和卵巢癌模型中的耐药性提供了一种可行的替代方案。这些发现为靶向具有扩增基因组位点的肿瘤提供了一般策略。