Triplex-forming oligonucleotides (TFO) were used to directly target amplified HER2 loci in breast tumors.
Major Finding: Triplex-forming oligonucleotides (TFO) were used to directly target amplified HER2 loci in breast tumors.
Concept: TFOs cause double stranded breaks and p53-independent apoptosis.
Impact: This approach to directly target amplified oncogene loci can be used to suppress the growth of various tumor types.
Although drugs targeting protein products of amplified oncogenic genes have proven to be effective anticancer therapies, drug resistance limits their overall success. Tiwari and colleagues developed an alternative strategy to target amplified oncogenes by using triplex-forming oligonucleotides (TFO), which recognize polypurine sites within the amplified chromosome region and cause double strand break (DSB) formation and apoptosis. While normal cells with low amplification of genes can withstand some DNA damage using the nucleotide excision repair (NER) pathway, cancer cells are less likely to with their high levels of gene amplification. When TFOs targeting HER2, a highly overexpressed gene in breast tumors, were introduced to HER2+ breast cancer cells, they bound specifically to HER2 chromosomal regions and increased levels of DNA damage as well as apoptosis. Furthermore, intraperitoneal administration of TFOs to immunosuppressed mice with HER2-amplified xenografts limited tumor growth at a comparable level to trastuzumab, a current treatment for HER2+ breast cancers. TFO efficacy was not limited by the genomic location of the polypurine target sites, with binding to intronic regions of HER2 also inducing DNA damage and apoptosis. Treatment with TFOs caused a similar level of PARP cleavage in p53-depleted human tumor cells as control cells, suggesting that TFO-induced proapoptosis was p53-independent. In addition, while trastuzumab causes reduction in total HER2 protein and changes to its tyrosine phosphorylation, TFO-treated breast cancer cell lines did not have significant changes in HER2 gene expression or phosphorylation levels, suggesting that the mechanism of TFO-induced apoptosis is p53 and HER2 expression independent. For enhanced drug delivery, polymeric, biodegradable nanoparticles (NP) were used to deliver HER2-targeted TFOs. TFOs delivered by NPs significantly accumulated within cancer cells at 12 hours post-administration, with a slight decrease at 24 hours. In addition, mice with HER2+ breast cancer xenografts showed significant reduction in tumor volume compared to control. In summary, this work describes a novel method to target amplified oncogenic genes in tumors as well as effective drug delivery and provides an alternative design for targeted therapies.
Tiwari MK, Colon-Rios DA, Tumu HCR, Liu Y, Quijano E, Krysztofiak A, et al. Direct targeting of amplified gene loci of proapoptotic anticancer therapy. Nat Biotechnol 2021 Oct 28 [Epub ahead of print].
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