Chordoma POLQ Drug Repurposing Hypothesis

Disease

Chordoma

Molecularly Defined Subset

Chordomas with evidence of POLQ dependency, potentially enriched by homologous recombination deficiency (HRD), DNA damage repair alterations, RAD51-foci failure, or PARP-resistant HRD biology.

Hypothesis

Can POLQ inhibitors (POLQi) treat POLQ-dependent chordoma by targeting TMEJ backup repair?

Drug

POLQ inhibitors (POLQi), including novobiocin as a repurposed parent concept and clinical-stage selective agents such as ART6043, GSK4524101, and MOMA-313.

Rationale

HRD Tumors Can Become Dependent On POLQ/TMEJ Backup Repair

  • Evidence: POLQ/TMEJ is a compensatory double-strand-break repair route when homologous recombination is impaired.
  • Sources: Zhou et al. 2021.

POLQi Have Shown Synthetic Lethality In HRD Tumor Models

  • Evidence: Novobiocin inhibited POLQ and selectively killed HRD breast and ovarian models in vitro and in vivo.
  • Sources: Zhou et al. 2021.

POLQi And PARPi Target Distinct DNA-Repair Vulnerabilities

  • Evidence: POLQi block TMEJ backup repair, while PARPi add PARP-mediated repair stress. Furthermore, PARP/TMZ sensitivity can reflect TMZ-associated base-damage repair rather than canonical HRD or POLQ dependency.
  • Sources: Zhou et al. 2021; Freed et al. 2022.

Chordoma Has An HRD Subset

  • Evidence: A 2019 Nature Communications study found HRD-associated mutational-signature enrichment in 8 of 11 advanced chordoma cases, with HR-pathway alterations including BRCA2, NBN, and CHEK2.
  • Sources: Groschel et al. 2019; Freed et al. 2022.

Prior POLQ Experiments Did Not Adequately Test Whether POLQi Benefit HRD-Biomarker-Positive Chordoma

  • Evidence: Chordoma Foundation tested ART558 across four chordoma cell lines. All had reported absolute EC50 values above 1 uM, and low-dose gemcitabine did not materially increase sensitivity. HRD controls were not established.
  • Sources: Chordoma Foundation figshare 2025.

Discussion

Prior negative testing in unselected chordoma models did not adequately test a molecularly defined POLQ-dependent subset.

This suggests the need to investigate whether POLQi could help a subset of chordoma patients.

Future investigations must first verify functional POLQ dependency. Candidate enrichment markers may include HRD, RAD51-foci failure, and PARP-resistant HRD biology.

References

  • Groschel et al. 2019. "Defective homologous recombination DNA repair as therapeutic target in advanced chordoma." Nature Communications. DOI: 10.1038/s41467-019-09633-9.
  • Freed et al. 2022. "Target discovery and drug repurposing opportunities in chordoma." Frontiers in Oncology. DOI: 10.3389/fonc.2022.1009193.
  • Zhou et al. 2021. "A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors." Nature Cancer. DOI: 10.1038/s43018-021-00203-x.
  • Chordoma Foundation figshare 2025. "Preclinical chordoma models are insensitive to DNA Polymerase theta inhibition, even when combined with replication stress inducer gemcitabine." DOI: 10.6084/m9.figshare.28964420.v2.
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