Homologous Repair‐Deficient Pancreatic Cancer: Refined Targeting of DNA Damage Response is an Effective Therapeutic Strategy

作者：Alica K. Beutel, Christopher J. Halbrook, Menar Ekizce, Jessica Lindenmayer, Élodie Roger, S. Calderón, Thomas Seufferlein, Alexander Kleger, Johann Gout, Lukas Perkhofer · 发表于：United European Gastroenterology Journal · 年份：2025 · DOI：10.1002/ueg2.12773 · 被引用次数：3 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、Lung Cancer Research Studies

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a high mortality rate. While up to 20% of PDAC patients harbor mutations in genes involved in homologous recombination (HR) repair, only 5% of germline BRCA1/2 mutation carriers have an approved treatment option with the PARP inhibitor (PARPi) olaparib. Characterizing HR-deficient (HRD) genotypes beyond gBRCA1/2 that are susceptible to PARPi has potential to substantially broaden the eligible patient population, and defining the optimal inhibitor may further optimize treatment strategies to advance personalized medicine in PDAC. OBJECTIVE: Our previous preclinical work showed synthetic lethality of a multi-pronged DNA damage repair interference strategy using the PARPi olaparib, ATR inhibitor VE-822, and DNA-PK inhibitor CC-115 (termed PAD) in ATM deficiency. In the present study, we challenged the role of olaparib in our PAD combination and assessed the regimen's efficacy across various HRD genotypes. METHODS: We assessed a spectrum of DNA damage repair-interfering drugs to identify the most potent inhibitor in HRD. Using ATM, BRCA1, BRCA2 and PALB2-defective versus HR-proficient murine PDAC cells, we systematically investigated the feasibility of expanding an optimized PAD regimen within defined HRD genotypes in vitro and in vivo. The regimen's efficacy was validated in PDAC patient-derived organoids with and without deleterious class IV/V alterations in HRD genes. RESULTS AND CONCLUSION: H...