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Published on: July 25, 2020
Selective DNA-PK Inhibition Enhances Chemotherapy and Ionizing Radiation Activity in Soft-Tissue Sarcomas
Audrey Laroche-Clary1,2, Coralie Josensi1,2, Marie-Alix Derieppe3
1Sarcoma Unit, Institut Bergonié, Bordeaux, France.
Purpose:
Patients with advanced soft-tissue sarcomas (STS) exhibit a poor prognosis and have few therapeutic options. DNA-dependent protein kinase (DNA-PK) catalytic subunit is a multifunctional serine-threonine protein kinase that plays a crucial role in DNA double-strand damage repair via nonhomologous end joining.
Experimental Design:
To investigate the therapeutic potential of DNA-PK targeting in STS, we first evaluated the prognostic value of DNA-PK expression in two large cohorts of patients with STS. We then used the potent and selective DNA-PK inhibitor AZD7648 compound to investigate the antitumor effect of the pharmacologic inhibition of DNA-PK in vitro via MTT, apoptosis, cell cycle, and proliferation assays. In vivo studies were performed with patient-derived xenograft models to evaluate the effects of AZD7648 in combination with chemotherapy or ionizing radiation on tumor growth. The mechanisms of sensitivity and resistance to DNA-PK inhibition were investigated by using a genome-wide CRISPR-Cas9 positive screen.
Results:
DNA-PK overexpression is significantly associated with poor prognosis in patients with sarcomas. Selective pharmacologic inhibition of DNA-PK strongly synergizes with radiation- and doxorubicin-based regimen in sarcoma models. By using a genome-wide CRISPR-Cas9 positive screen, we identified genes involved in sensitivity to DNA-PK inhibition.
Conclusions:
DNA-PK inhibition deserves clinical investigation to improve response to current therapies in patients with sarcoma.
Insights
Targeting DNA-dependent protein kinase (DNA-PK) shows promise for soft-tissue sarcomas (STS). Inhibiting DNA-PK synergizes with chemotherapy and radiation, suggesting its clinical investigation for improved STS treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Advanced soft-tissue sarcomas (STS) have limited treatment options and poor prognoses.
- DNA-dependent protein kinase (DNA-PK) is crucial for DNA repair and implicated in cancer progression.
Purpose of the Study:
- To evaluate DNA-PK as a therapeutic target in STS.
- To assess the prognostic value of DNA-PK expression in STS patients.
- To investigate the antitumor effects of DNA-PK inhibition.
Main Methods:
- Assessed DNA-PK expression in STS patient cohorts.
- Utilized the DNA-PK inhibitor AZD7648 in vitro (MTT, apoptosis, cell cycle, proliferation assays).
- Conducted in vivo studies with patient-derived xenografts, combining AZD7648 with chemotherapy or radiation.
- Employed genome-wide CRISPR-Cas9 screening to identify sensitivity/resistance mechanisms.
Main Results:
- Elevated DNA-PK expression correlated with poor prognosis in sarcoma patients.
- Pharmacologic DNA-PK inhibition demonstrated strong synergy with radiation and doxorubicin in sarcoma models.
- Identified key genes influencing sensitivity to DNA-PK inhibition via CRISPR screening.
Conclusions:
- DNA-PK inhibition warrants clinical investigation for enhancing current sarcoma therapies.
- Targeting DNA-PK represents a promising strategy to improve treatment response in STS patients.
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