Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer

Abstract

Antimetabolite chemotherapy remains an essential cancer treatment modality, but often produces only marginal benefit due to the lack of tumor specificity, the development of drug resistance, and the refractoriness of slowly-proliferating cells in solid tumors. Here, we report a novel strategy to circumvent the proliferation-dependence of traditional antimetabolite-based therapies. Triplex-forming oligonucleotides (TFOs) were used to target site-specific DNA damage to the human c-MYC oncogene, thereby inducing replication-independent, unscheduled DNA repair synthesis (UDS) preferentially in the TFO-targeted region. The TFO-directed UDS facilitated incorporation of the antimetabolite, gemcitabine (GEM), into the damaged oncogene, thereby potentiating the anti-tumor activity of GEM. Mice bearing COLO 320DM human colon cancer xenografts (containing amplified c-MYC) were treated with a TFO targeted to c-MYC in combination with GEM. Tumor growth inhibition produced by the combination was significantly greater than with either TFO or GEM alone. Specific TFO binding to the genomic c-MYC gene was demonstrated, and TFO-induced DNA damage was confirmed by NBS1 accumulation, supporting a mechanism of enhanced efficacy of GEM via TFO-targeted DNA damage-induced UDS. Thus, coupling antimetabolite chemotherapeutics with a strategy that facilitates selective targeting of cells containing amplification of cancer-relevant genes can improve their activity against solid tumors, while possibly minimizing host toxicity.

LncRNA MIR100HG promotes cell proliferation in triple-negative breast cancer through triplex formation with p27 loci

“…For example, they can act as anchors to recruit DNA methylation enzymes or histone-modifying proteins to specific sites in chromatin 38 , 39 , which can, in turn, regulate gene transcription. TFOs serve as transcriptional suppressors and can downregulate gene expression in cancer 29 , 45 – 47 . For example, TFOs directed to a particular sequence in the Ets2 promoter can repress transcription of this gene, thereby inducing growth inhibition and apoptosis in prostate cancer 46 .…”

Oligonucleotide Therapies: The Past and the Present

“… 135 So far, TFOs have not been used clinically, but it was recently reported that a TFO targeting the MYC promoter in combination with gemcitabine potentiated the antitumor activity in a mouse model. 136 …”

Suppression of c-Myc and RRM2 expression in pancreatic cancer cells by the sphingosine kinase-2 inhibitor ABC294640

“…Another key protein that regulates pancreatic cancer cell sensitivity to gemcitabine is c-Myc, a central transcription factor with a plethora of target genes that play roles in proliferation, mitochondrial biogenesis, and glucose metabolism. The MYC proto-oncogene is overexpressed in many types of cancer [ 9 ], including pancreatic cancer [ 10 ] where it has been shown to decrease sensitivity to gemcitabine [ 11 , 12 ].…”