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Peer-reviewedCC BY 4.0Frontiers in Pharmacology

Beyond classical synthetic lethality: how PARP inhibitor pharmacology contributes to antitumor activity in HR-proficient cancers

  • Yan Han1,2
  • Mengqi Li3,4
  • Yuting Su1,2,4
  • Yuwei Lu1,2
  • Jinyue Shan3
  • Xia Liu2,5,6
  • Fuqiang Yin3,7
7 affiliations
  1. 1Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University
  2. 2Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Institute of Neuroscience and Guangxi Key Laboratory of Brain Science, School of Basic Medical Sciences, Guangxi Medical University
  3. 3Life Sciences Institute, Guangxi Medical University
  4. 4Affiliated Tumor Hospital, Guangxi Medical University
  5. 5Education Department of Guangxi Zhuang Autonomous Region, Key Laboratory of Human Development and Disease Research (Guangxi Medical University)
  6. 6Guangxi Health Commission Key Laboratory of Basic Research on Brain Function and Disease
  7. 7Key Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education
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Abstract

PARP inhibitors were developed on the principle of synthetic lethality, which predicts enhanced sensitivity in tumors with homologous recombination deficiency (HRD). Clinical trials have demonstrated benefits beyond germline BRCA-mutated disease (NOVA and ARIEL3), including modest progression-free survival improvements in genomically HRD-negative subgroups (PRIMA). However, negative genomic HRD testing does not necessarily indicate functional HR proficiency, and these findings do not establish mechanisms independent of synthetic lethality. This Review examines the pharmacological mechanisms that may contribute to PARP inhibitor activity beyond established BRCA-associated HRD. The four agents have distinct pharmacological profiles—differences in PARP trapping potency, off-target activities against kinases (DYRK1A/1B, PIM3, CDK16) and the non-kinase PARP16, and immune-modulatory effects—that extend activity beyond HRD. Beyond canonical BRCA-associated HRD, these activities map onto distinct conditional dependencies in individual tumor contexts: lineage-dependent oncoprotein stability in small cell lung cancer, genotype-dependent immune vulnerability in SPOP-mutant prostate cancer, and pharmacologically induced HR impairment in hepatocellular carcinoma, where a direct c-Met–PARP1 mechanism remains to be verified. On-target mechanisms (PARP trapping and downstream DNA-damage effects) are directly demonstrated, whereas individual off-target contributions to clinical efficacy remain largely correlative and require prospective validation. By organizing these mechanisms into a unifying framework, this review aims to guide off-target-aware PARP inhibitor selection, rational combination design, and the development of next-generation compounds, providing a framework for investigating context-dependent PARP inhibitor strategies beyond established HRD-associated indications.

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Cite

BibTeXRIS
BibTeX
@article{han2026beyond,
  title = {{Beyond classical synthetic lethality: how PARP inhibitor pharmacology contributes to antitumor activity in HR-proficient cancers}},
  author = {Yan Han and Mengqi Li and Yuting Su and Yuwei Lu and Jinyue Shan and Xia Liu and Fuqiang Yin},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = nov,
  doi = {10.3389/fphar.2026.2003744},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.2003744/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Beyond classical synthetic lethality: how PARP inhibitor pharmacology contributes to antitumor activity in HR-proficient cancers
AU  - Yan Han
AU  - Mengqi Li
AU  - Yuting Su
AU  - Yuwei Lu
AU  - Jinyue Shan
AU  - Xia Liu
AU  - Fuqiang Yin
PY  - 2026
DA  - 2026/11/03
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.2003744
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.2003744/full
AB  - PARP inhibitors were developed on the principle of synthetic lethality, which predicts enhanced sensitivity in tumors with homologous recombination deficiency (HRD). Clinical trials have demonstrated benefits beyond germline BRCA-mutated disease (NOVA and ARIEL3), including modest progression-free survival improvements in genomically HRD-negative subgroups (PRIMA). However, negative genomic HRD testing does not necessarily indicate functional HR proficiency, and these findings do not establish mechanisms independent of synthetic lethality. This Review examines the pharmacological mechanisms that may contribute to PARP inhibitor activity beyond established BRCA-associated HRD. The four agents have distinct pharmacological profiles—differences in PARP trapping potency, off-target activities against kinases (DYRK1A/1B, PIM3, CDK16) and the non-kinase PARP16, and immune-modulatory effects—that extend activity beyond HRD. Beyond canonical BRCA-associated HRD, these activities map onto distinct conditional dependencies in individual tumor contexts: lineage-dependent oncoprotein stability in small cell lung cancer, genotype-dependent immune vulnerability in SPOP-mutant prostate cancer, and pharmacologically induced HR impairment in hepatocellular carcinoma, where a direct c-Met–PARP1 mechanism remains to be verified. On-target mechanisms (PARP trapping and downstream DNA-damage effects) are directly demonstrated, whereas individual off-target contributions to clinical efficacy remain largely correlative and require prospective validation. By organizing these mechanisms into a unifying framework, this review aims to guide off-target-aware PARP inhibitor selection, rational combination design, and the development of next-generation compounds, providing a framework for investigating context-dependent PARP inhibitor strategies beyond established HRD-associated indications.
SN  - 1663-9812
ER  -