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Heterogeneity and Clonal Evolution of Acquired PARP Inhibitor Resistance in TP53- and BRCA1-Deficient Cells

Anniina Färkkilä1,2,3, Alfredo Rodríguez1,4, Jaana Oikkonen3

  • 1Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Cancer Research
|January 30, 2021
PubMed

Insights

Acquired resistance to poly-ADP ribose polymerase inhibitors (PARPi) in homologous recombination-deficient cancers arises from diverse, genomically unstable clones. Targeting these resistant cells requires understanding their specific vulnerabilities for effective therapy.

Area of Science:

  • Genomics and Cancer Biology
  • Drug Resistance Mechanisms
  • Precision Oncology

Background:

  • Homologous recombination (HR)-deficient cancers, including high-grade serous ovarian cancers (HGSC), are initially sensitive to poly-ADP ribose polymerase inhibitors (PARPi).
  • Acquired resistance to PARPi is a significant clinical challenge, leading to treatment relapse in the majority of patients.
  • Understanding the heterogeneity and evolution of PARPi resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the mechanisms and heterogeneity of acquired PARPi resistance in BRCA1-deficient epithelial cells.
  • To analyze the genomic and transcriptional profiles of PARPi-resistant clones.
  • To identify potential therapeutic vulnerabilities in PARPi-resistant cancer cells.

Main Methods:

  • Generation of seven single-cell clones with acquired PARPi resistance from a TP53-/- and BRCA1-/- epithelial cell line using CRISPR/Cas9.
  • Comprehensive genomic and transcriptional profiling of sensitive and resistant cell lines.
  • Clonal evolutionary analysis and imaging-based drug screening of resistant clones.

Main Results:

  • Acquired PARPi resistance is driven by diverse mechanisms, with some clones exhibiting multiple resistance pathways simultaneously.
  • PARPi-resistant clones display distinct transcriptional and mutational profiles, alongside increased genomic instability compared to sensitive cells.
  • Clonal heterogeneity and drug-tolerant cells within the sensitive population contribute to the emergence of resistance.
  • Tumor biopsies from patients with acquired PARPi resistance show similar clonal and spatial heterogeneity.
  • Resistant clones exhibit heterogeneous responses to targeted agents, highlighting mechanism-dependent vulnerabilities.

Conclusions:

  • BRCA1-deficient cells can generate multiple, genomically and functionally diverse PARPi-resistant clones.
  • Acquired resistance evolves through clonal selection from an inherently unstable and heterogeneous cell population.
  • Mechanism-specific targeting strategies and biomarkers are needed to overcome PARPi resistance in HGSC.

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