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Background <p>Poly(ADP-ribose) polymerase (PARP) inhibitors are highly effective therapies for BRCA1/2-mutated tumors. However, most patients eventually develop acquired resistance. Here, we report that JPI-547, a second-generation PARP inhibitor targeting both PARP1/2 and tankyrase, demonstrates potent antitumor activity in olaparib-sensitive and resistant BRCA1/2 mutant models.</p> Methods <p>Olaparib-resistant (OR) models were generated using BRCA-mutated human ovarian and breast cancer cell lines and ovarian Patient-Derived Tumor Xenograft (PDTX) by exposing to olaparib. For clinical relevance, public mRNA microarray datasets of ovarian and breast cancer were analyzed.</p> Results <p>JPI-547 demonstrated better antitumor efficacy in both olaparib-sensitive and resistant BRCA-mutated preclinical models than first-generation PARP inhibitors. Mechanistically, the on-target inhibition of PARP1/2 and tankyrase by JPI-547 strongly inhibited the restoration of homologous recombination (HR) activity by suppressing RAD51 expression. This action resulted in the retardation of tumor growth in olaparib-sensitive and resistant ovarian PDTX models. Furthermore, high RAD51 expression was significantly associated with poor prognosis in ovarian and breast cancer patients based on public mRNA expression data.</p> Conclusion <p>These results suggest the scientific rationale for further clinical development of JPI-547 for treating both PARP inhibitor-sensitive patients and those resistant to first-generation PARP inhibitors in BRCA-mutated cancers.</p>

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JPI-547, a novel dual inhibitor of PARP1/2 and tankyrase is more effective than first-generation PARP inhibitors in preclinical BRCA1/2-mutated cancer models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月6日

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  • Min Sil Kang,
  • Nar Bahadur Katuwal,
  • Mithun Ghosh,
  • Sa Deok Hong,
  • Yeong Gyu Jeong,
  • Seong Min Park,
  • Tae Hoen Kim,
  • Seul-Gi Kim,
  • Seung Ryeol Lee,
  • Yong Wha Moon

摘要

Background

Poly(ADP-ribose) polymerase (PARP) inhibitors are highly effective therapies for BRCA1/2-mutated tumors. However, most patients eventually develop acquired resistance. Here, we report that JPI-547, a second-generation PARP inhibitor targeting both PARP1/2 and tankyrase, demonstrates potent antitumor activity in olaparib-sensitive and resistant BRCA1/2 mutant models.

Methods

Olaparib-resistant (OR) models were generated using BRCA-mutated human ovarian and breast cancer cell lines and ovarian Patient-Derived Tumor Xenograft (PDTX) by exposing to olaparib. For clinical relevance, public mRNA microarray datasets of ovarian and breast cancer were analyzed.

Results

JPI-547 demonstrated better antitumor efficacy in both olaparib-sensitive and resistant BRCA-mutated preclinical models than first-generation PARP inhibitors. Mechanistically, the on-target inhibition of PARP1/2 and tankyrase by JPI-547 strongly inhibited the restoration of homologous recombination (HR) activity by suppressing RAD51 expression. This action resulted in the retardation of tumor growth in olaparib-sensitive and resistant ovarian PDTX models. Furthermore, high RAD51 expression was significantly associated with poor prognosis in ovarian and breast cancer patients based on public mRNA expression data.

Conclusion

These results suggest the scientific rationale for further clinical development of JPI-547 for treating both PARP inhibitor-sensitive patients and those resistant to first-generation PARP inhibitors in BRCA-mutated cancers.