Open AccessDirect targeting of amplified gene loci for proapoptotic anticancer therapy
Author(s) -
Meetu Kaushik Tiwari,
Daniel A. Colon-Rios,
Hemanta C. Rao Tumu,
Yanfeng Liu,
Elias Quijano,
A. Krysztofiak,
Ckk Chan,
Eric Song,
Demetrios T. Braddock,
Hee-Won Suh,
W. Mark Saltzman,
Faye A. Rogers
Publication year - 2021
Publication title -
nature biotechnology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.358
H-Index - 445
eISSN - 1546-1696
pISSN - 1087-0156
DOI - 10.1038/s41587-021-01057-5
Subject(s) - gene , genetic enhancement , genetics , biology , cancer research , computational biology
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.