TMPRSS2:ERG Gene Fusion Might Predict Resistance to PARP Inhibitors in Metastatic Castration-resistant Prostate Cancer

Tim Svenstrup Poulsen*, Anders Nygaard Lørup, Per Kongsted, Rikke Løvendahl Eefsen, Martin Højgaard, Estrid Vilma Høgdall

*Corresponding author for this work

Abstract

BACKGROUND/AIM: The emergence of novel DNA damage repair (DDR) pathways in molecular-target therapy drugs (MTTD) has shown promising outcomes in treating patients with metastatic castration-resistant prostate cancer (mCRPC). About 25% of mCRPC patients have actionable deleterious aberrations in DDR genes, primarily in the homologous recombination (HR) pathway. However, the response rate in patients with BRCA1/2 or mutations in HRR-related genes is only 45%-55%, when exposed to poly ADP ribose polymerase (PARP) inhibitor-based therapy (PARPi). A frequent characteristic feature of prostate cancer (PC) is the occurrence of genomic rearrangement that affects the transmembrane protease serine 2 (TMPRSS2) and E26 transformation-specific (ETS)- transcription factor-related gene (ERG).

MATERIALS AND METHODS: In this study, a total of 114 patients with mCRPC had their RNA and DNA sequenced using next-generation sequencing.

RESULTS: Based on their genetic profile of deleterious gene alterations of BRCA1/2 or ATM, six patients were selected for PARPi. Patients with TMPRSS2:ERG gene fusion and homozygous alteration in ATM or BRCA2 (n=2) or heterozygous alterations (BRCA1 or BRCA2) and lack of TMPRSS2:ERG gene fusion (n=2) did not show clinical benefit from PARPi (treatment duration <16 weeks). In contrast, patients (n=2) without TMPRSS2:ERG gene fusion and homozygous deleterious alterations in ATM or BRCA2 all had clinical benefit from PARPi (treatment duration ≥16 weeks).

CONCLUSION: The TMPRSS2:ERG transcript product might be used as a PARPi resistance biomarker.

Original languageEnglish
JournalAnticancer Research
Volume44
Issue number10
Pages (from-to)4203-4211
Number of pages9
ISSN0250-7005
DOIs
Publication statusPublished - Oct 2024

Keywords

  • Humans
  • Male
  • Prostatic Neoplasms, Castration-Resistant/genetics
  • Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
  • Drug Resistance, Neoplasm/genetics
  • Oncogene Proteins, Fusion/genetics
  • Aged
  • Serine Endopeptidases/genetics
  • Middle Aged
  • BRCA2 Protein/genetics
  • BRCA1 Protein/genetics

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