Abstract 4773: Gene-targeted apoptosis as a novel therapeutic strategy for HER2-positive breast cancer

Abstract

Abstract The ability to target HER2-driven breast cancers using anticancer agents with mechanisms of actions that are independent of the HER2 cellular growth function, represents a powerful new tool to circumvent drug resistance experienced with traditional HER2-targeted therapies. We have discovered that manipulation of the balance between the DNA repair response and apoptotic pathways provides an alternative strategy to induce targeted apoptosis in HER2-amplified breast cancers. Our recent finding that triplex-induced DNA damage can activate apoptosis in human cells has yielded the opportunity to develop a new class of HER2-targeted therapies. Here, we have uncovered the novel finding that triplex-induced apoptosis only occurs when multiple triplex structures are formed, while NER (nucleotide excision repair)-dependent repair prevails in the presence of one or two structures. With this in mind, we have designed sequence-specific DNA-binding molecules that create chromosomal triplex structures and activate tumor-specific apoptosis through the induction of excessive DNA damage at the HER2 locus. Importantly, this only occurs in malignant cells with multiple copies of the HER2 gene. We have evaluated the efficacy of the HER2-targeted triplex-forming molecules using cell growth and apoptosis assays and demonstrate that these molecules are particularly effective in eliciting tumor specific apoptosis in HER2-amplified breast cancer cell lines. Furthermore, these molecules have the ability to suppress the growth and metastasis of human HER2-positive breast cancers in a xenograft mouse model. Moreover, we demonstrate that the NER protein, XPD mediates the survival-death decision in response to triplex-induced DNA damage via a p53-independent mechanism that involves phosphorylation of the H2AX tyrosine 142 residue, which stimulates the signaling pathway to recruit pro-apoptotic factors to the damage site. Our results establish an alternative and novel method to specifically target HER2-positive breast cancers by exploiting the cell's own DNA damage response machinery. This study introduces a new paradigm for gene-targeted drugs that can be used in the treatment of HER2-positive and drug-resistant breast cancers with minimal potential for toxicity to normal tissue. Citation Format: Faye A. Rogers, Meetu Kaushik. Gene-targeted apoptosis as a novel therapeutic strategy for HER2-positive breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4773.