PubReading [277] - Direct targeting of amplified gene loci for proapoptotic anticancer therapy - M. Tiwari, F. Rogers at al..

<p><strong>Gene amplification</strong> 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 (<strong>TFO</strong>s), which drive the induction of apoptosis in tumors, whereas cells without amplifications process lower levels of DNA damage. Focusing on cancers driven by <strong><em>HER2</em></strong><em> </em>amplification, we find that TFOs targeting <em>HER2 </em>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 <strong>genomic loci</strong>.</p><p><a href="https://doi.org/10.1038/s41587-021-01057-5"><em>https://doi.org/10.1038/s41587-021-01057-5</em></a><em> - 2022</em></p>