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HER2 amplification in breast cancer is associated with a more aggressive disease, greater likelihood of recurrence, and decreased survival compared to women with HER2-negative breast cancer. Trastuzumab is a monoclonal antibody that inhibits HER2 activity, making this compound an important therapeutic option for patients with HER2-positive breast cancer. However, resistance to trastuzumab develops rapidly in a large number of breast cancer patients. The objective of this study was to determine whether GRN163L, a telomerase template antagonist currently in clinical trials for cancer treatment, can augment the effects of trastuzumab in breast cancer cells with HER2 amplification. GRN163L was effective in inhibiting telomerase activity and shortening telomeres in HER2-positive breast cancer cells. We show that GRN163L acts synergistically with trastuzumab in inhibiting HER2-positive breast cancer cell growth. More importantly, we show that GRN163L can restore the sensitivity of therapeutic-resistant breast cancer cells to trastuzumab. These findings implicate that telomerase template antagonists have potential use in the treatment of cancers that have developed resistance to traditional cancer therapy.

Telomeres are repetitive (TTAGGG)(n) DNA sequences found at the end of chromosomes that protect the ends from recombination, end to end fusions, and recognition as damaged DNA. Telomerase activity can be detected in 85% to 90% of human tumors, which stabilizes telomeres to prevent apoptosis or cellular senescence. Previous reports showed the efficacy of the novel telomerase template antagonist, GRN163L, as a potential anticancer agent. The objective of the present study was to elucidate the molecular effects of GRN163L in MDA-MB-231 breast cancer cells and to determine whether GRN163L could be used in mechanism-based combination therapy for breast cancer. We observed that GRN163L reduced MDA-MB-231 growth rates without a significant effect on breast cancer cell viability within the first 14 days in vitro. In addition, GRN163L altered cell morphology, actin filament organization, and focal adhesion formation in MDA-MB-231 cells. Importantly, the cellular response to GRN163L significantly augmented the effects of the microtubule stabilizer paclitaxel in MDA-MB-231 breast cancer cell growth in vitro and in vivo compared with paclitaxel alone or a mismatch control oligonucleotide plus paclitaxel. Furthermore, in vitro MDA-MB-231 invasive potential was significantly inhibited with GRN163L and paclitaxel. These data support a rationale for potentially combining GRN163L with paclitaxel for the treatment of breast cancer in the clinical setting.