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Updated: Jun 10, 2025

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Poly (ADP-ribose) Polymerase Inhibitor Resistance Driven by Emergence of Polyclonal Mutations With Convergent

Maria Fatteh1,2, Jaime Wehr1,2, Katerina Karaindrou1,2

  • 1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.

JCO Precision Oncology
|October 11, 2024
PubMed

Insights

This study observed polyclonal, convergent evolution leading to PARPi resistance in a metastatic breast cancer patient with a germline PALB2 mutation. This highlights a complex resistance mechanism in PARP inhibitor therapy.

Area of Science:

  • Oncology
  • Genetics
  • Cancer Biology

Background:

  • Metastatic breast cancer (MBC) poses significant treatment challenges.
  • Germline mutations in PALB2 are associated with hereditary breast cancer and influence treatment response.
  • PARP inhibitors (PARPi) are a targeted therapy for certain breast cancers, but resistance can develop.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to PARP inhibitors (PARPi) in a patient with metastatic breast cancer and a germline PALB2 mutation.
  • To characterize the genetic evolution of tumor cells under PARPi treatment.

Main Methods:

  • Longitudinal tumor biopsy analysis.
  • Next-generation sequencing (NGS) to identify genetic alterations.
  • Clonal evolution analysis to track tumor heterogeneity.

Main Results:

  • Demonstrated polyclonal, convergent evolution of resistance mechanisms.
  • Identified distinct genetic events arising independently in multiple tumor cell clones.
  • These events collectively conferred resistance to PARP inhibitors.

Conclusions:

  • Acquired resistance to PARPi in this PALB2-mutated breast cancer patient was driven by polyclonal, convergent evolution.
  • Understanding these complex resistance pathways is crucial for developing effective therapeutic strategies.

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