Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies

Diana Restifo, Joseph R. McDermott, Dusica Cvetkovic, Troy Dos Santos, Charline Ogier, Aizhan Surumbayeva, Elizabeth A. Handorf, Caleb Schimke, Charlie Ma, Kathy Q. Cai, Anthony J. Olszanski, Umesh Kathad, Kishor Bhatia, Panna Sharma, Aditya Kulkarni, Igor Astsaturov

Research output: Contribution to journalArticlepeer-review

Abstract

The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways. Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared with DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1, and BRCA2. Depletion of PTGR1, however, completely abrogates the antitumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy. Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184.

Original languageEnglish
Pages (from-to)1182-1190
Number of pages9
JournalMolecular Cancer Therapeutics
Volume22
Issue number10
DOIs
StatePublished - Oct 1 2023

Keywords

  • Adenocarcinoma
  • Alcohol Oxidoreductases/genetics
  • Animals
  • Antineoplastic Agents/pharmacology
  • DNA Damage
  • DNA Repair
  • Humans
  • Pancreatic Neoplasms/drug therapy

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