Peposertib, a DNA-PK Inhibitor, Enhances the Anti-Tumor Efficacy of Topoisomerase II Inhibitors in Triple-Negative
Steffie Revia1, Felix Neumann1, Julia Jabs1
1Research Unit Oncology, Merck Healthcare KGaA, Darmstadt, Germany.
Abstract:
Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients.
Insights
Peposertib, a DNA-PK inhibitor, shows promise in enhancing chemotherapy for triple-negative breast cancer (TNBC). Combining peposertib with anthracyclines synergistically reduced cancer cell growth and tumor size in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited treatment options.
- Current anthracycline/taxane chemotherapy offers suboptimal outcomes for most TNBC patients.
- There is a critical need for novel strategies to improve TNBC chemotherapy efficacy.
Purpose of the Study:
- To investigate the potential of peposertib, a DNA-PK inhibitor, to enhance the effectiveness of topoisomerase II (TOPO II) inhibitors in TNBC.
- To evaluate the synergistic effects of peposertib in combination with anthracyclines and other TOPO II inhibitors.
- To assess the preclinical efficacy of peposertib combined with pegylated liposomal doxorubicin (PLD) in TNBC models.
Main Methods:
- In vitro studies using multiple TNBC cell lines to assess synergistic antiproliferative activity.
- Analysis of downstream signaling pathways, including ATM and p53 activation.
- In vivo studies using mouse xenograft models (cell-line-derived and patient-derived) to evaluate anti-tumor effects of combination therapy.
Main Results:
- Peposertib demonstrated synergistic antiproliferative effects when combined with doxorubicin, epirubicin, and etoposide in TNBC cell lines.
- Combination treatment induced ATM-dependent compensatory signaling and p53 pathway activation.
- A well-tolerated preclinical regimen of peposertib and PLD showed strong anti-tumor efficacy in vivo.
Conclusions:
- Peposertib can enhance the efficacy of anthracycline/TOPO II-based chemotherapies in TNBC.
- Combination therapy with peposertib represents a promising strategy to improve treatment outcomes for TNBC patients.
- Further clinical investigation of peposertib in combination regimens for TNBC is warranted.
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