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Reversion Mutations with Clinical Use of PARP Inhibitors: Many Genes, Many Versions

Susan M Domchek1

  • 1Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. susan.domchek@uphs.upenn.edu.

Cancer Discovery
|September 3, 2017
PubMed

Insights

PARP inhibitor resistance in cancer can be caused by reversion mutations in genes like BRCA1/2, RAD51C/D, and PALB2. These diverse mutations can be detected in circulating cell-free DNA, offering new insights into treatment resistance.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • PARP inhibitors are crucial in treating cancers with homologous recombination deficiency (HRD), often linked to BRCA1/2 mutations.
  • Tumor resistance to PARP inhibitors can emerge due to secondary genetic alterations.
  • Reversion mutations restoring homologous recombination function are a known mechanism of resistance.

Purpose of the Study:

  • To identify and characterize reversion mutations in genes beyond BRCA1/2 that confer PARP inhibitor resistance.
  • To investigate the occurrence and diversity of these mutations within individual patients.
  • To assess the utility of circulating cell-free DNA (cfDNA) for detecting these resistance mechanisms.

Main Methods:

  • Somatic mutation profiling of tumors from patients with PARP inhibitor resistance.
  • Targeted sequencing and whole-exome sequencing to identify reversion mutations.
  • Analysis of circulating cell-free DNA (cfDNA) to detect emergent mutations.

Main Results:

  • Reversion mutations were identified in RAD51C, RAD51D, and PALB2, in addition to BRCA1 and BRCA2.
  • Multiple distinct reversion mutations were observed within the same patient.
  • Detection of these reversion mutations was feasible through cfDNA analysis.

Conclusions:

  • Reversion mutations in a broader range of genes contribute to PARP inhibitor resistance.
  • The presence of multiple reversion mutations in a single patient highlights complex resistance pathways.
  • Circulating cell-free DNA analysis is a promising non-invasive method for monitoring resistance evolution.

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