Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Childhood and adult solid tumors have unsatisfactory cure rates, often due to chemotherapy resistance and undefined molecular targets.
• The DNA transposase PGBD5 is expressed in many childhood solid tumors, including neuroblastoma and medulloblastoma.
• Nonhomologous end joining (NHEJ) DNA repair is crucial for tolerating PGBD5 expression.

Purpose of the Study:

• To identify therapeutic vulnerabilities in PGBD5-expressing solid tumors.
• To investigate the role of PGBD5 in DNA damage and cell death.
• To evaluate AZD6738 as a potential therapeutic agent for PGBD5-driven cancers.

Main Methods:

• Functional genetic approaches to assess PGBD5 in NHEJ-deficient cells.
• Chemical screening for inhibitors sensitizing PGBD5-expressing cells to DNA damage.
• In vitro and in vivo studies using tumor cell lines and patient-derived xenografts.
• Assessing apoptosis and tumor regression in response to AZD6738, alone and with cisplatin.

Main Results:

• PGBD5 expression induces sensitivity to DNA damage and apoptosis, particularly in NHEJ-deficient cells.
• AZD6738 was identified as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis.
• PGBD5-expressing tumor cells showed increased unrepaired DNA damage and apoptosis upon AZD6738 treatment.
• AZD6738 demonstrated nanomolar potency against neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdoid tumor cells in vitro.
• In vivo, AZD6738 induced tumor regression, potentiated by cisplatin, including against patient-derived xenografts.

Conclusions:

• PGBD5 expression creates a synthetic dependency in solid tumors, making them vulnerable to specific therapeutic interventions.
• AZD6738 represents a promising targeted therapy for PGBD5-expressing solid tumors.
• Combination therapy with AZD6738 and cisplatin shows significant potential for treating aggressive childhood cancers.