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Modelling treatment resistance in ovarian cancer: exploring the PEO series

Why the PEO series matters in ovarian cancer research

In high-grade serous ovarian cancer (HGSC), BRCA2 mutations impair DNA repair via homologous recombination (HR), creating initial sensitivity to platinum-based chemotherapy and PARP inhibitors (PARPi) (1).  Resistance often emerges through secondary BRCA2 mutations that restore HR (2). This functional change is detectable via RAD51 foci formation, a widely used marker of HR competence. Studying this evolution is key to understanding and overcoming acquired drug resistance. 

The PEO series uniquely models this trajectory. PEO1, PEO4, and PEO6 were derived from the same patient at different treatment stages. PEO1-OR, selected in vitro for olaparib resistance, extends the series by providing a model of acquired PARPi resistance. Together, these lines offer matched, mechanistically distinct models for investigating DNA repair mechanisms, drug resistance pathways, and response prediction in ovarian cancer. 

Clinical course of the patient from which PEO1, PEO4 and PEO6 were derived,
Image adapted from Sakai et al. 2009. PMID: 19654294. Clinical course of the patient from which PEO1, PEO4 and PEO6 were derived, with timings of sample collection used to generate cell lines. *PEO1-OR was derived from PEO1 through stepwise exposure to increasing olaparib concentrations.

Patient-matched PEO lines: modelling tumour evolution and drug resistance

 

 
PEO1 
PEO1-OR 
PEO4 
PEO6 
Patient origin and treatment
From ascites of a poorly differentiated serous ovarian adenocarcinoma at first relapse, after chemotherapy (3, 4)
In vitro  derivative of PEO1 selected for olaparib (PARPi) resistance (5)
From ascites of PEO1 patient, but after multiple chemotherapies (3,6)
From ascites of PEO1 patient, but at a later relapse (post-chemotherapy) (3,6)
BRCA2 status
Homozygous nonsense Y1655X mutation (5193C>G) causing loss of full-length BRCA2 protein (4)
Secondary mutation during selection restored the full-length HR-proficient BRCA2 protein​ (5)
Secondary synonymous Y1655Y change (5193C>T) restored HR-proficient full-length BRCA2 protein (4)
Same 5193C>T silent change of PEO4, restored HR-proficient full-length BRCA2 protein (4)
HR capacity
Deficient with no BRCA2 protein (4)
Restored HR function and RAD51 foci–positive (5)
Restored HR function and RAD51 foci–positive (4,5)
Expected to be RAD51 foci–positive (HR-proficient) due to its BRCA2 functionality (4)
Platinum sensitivity
Cisplatin-sensitive before resistance (3)
Expected to be cross-resistant to platinum due to restored BRCA2
Cisplatin resistant (7)
Cisplatin resistant (4)
PARPi sensitivity
Highly sensitive to olaparib and veliparib (8)
Selected for Olaparib resistance (5)
Resistant to AG14361 (4) and veliparib (8)
Resistant to olaparib and veliparib (8)
Tumorigenicity
Tumourigenic in immunodeficient mice (xenograft-forming) (3)
Not tested in vivo
Tumourigenic in immunodeficient mice (xenograft-forming) (3)
Tumourigenic in immunodeficient mice (xenograft-forming) (3)
Model use
HRD benchmarking
PARPi resistance modelling
Reverted HR-comparator
Late-stage resistance
Abbreviations in the table: HR: homologous repair, HRD: homologous repair deficiency, PARPi: PARP inhibitor.

Complementary PEO lines from other patients

In addition to the patient-matched PEO1-PEO6 series, PEO14, PEO16, and PEO23 offer HR-proficient models with either wild-type or mildly altered but functionally intact BRCA2, providing a valuable comparison to BRCA2-deficient lines such as PEO1. 

  • PEO14 and PEO23 from a patient-matched, platinum-sensitive pair (pre-treatment and relapse) with wild-type BRCA2, enabling studies of non-BRCA2-driven resistance and serving as controls in HRD and PARPi assays (3, 9).  
  • PEO16, although carrying a BRCA2 variant, retains HR activity and serves as an additional functional comparator (10). 

References

  1. González-Martín A. Lancet Oncol. 2017;18(1):8–9. PMID: 27908593
  2. Paes Dias M, et al. Nat Rev Clin Oncol. 2021;18(12):773–791. PMID: 34285417
  3. Langdon et al. 1988. Cancer Research. 48(21):6166–6172. PMID: 3167863
  4. Sakai et al. 2009. Cancer Research. 69(16):6381–6386. PMID: 19654294
  5. Biegala et al. 2023. Cells. 12(7), 1038. PMID: 37048111
  6. Greenwood et al. Clin Cancer Res. 2019. 25(8):2471-2482. PMID: 30651275
  7. Zhihong et al. 2016. Cancer Lett. 19;373(1):36–44. PMID: 26801746
  8. Stukova et al. 2015. J Inorg Biochem. 149:45-8. PMID: 26021697
  9. Ng CKY et al. 2012. J. Pathol. 226(5):703-12. PMID: 22183581.
  10. Meijer TG et al. 2024. Cancers (Basel). 16(4):741. PMID: 38398132.

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