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<p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy driven predominantly by KRAS mutations, with KRAS<sup>G12D</sup> present in ~40 % of cases. Although the selective KRAS<sup>G12D</sup> inhibitor MRTX1133 shows promising activity, monotherapy responses are incomplete and resistance emerges rapidly. In this study, we show that KRAS<sup>G12D</sup> blockade suppresses homologous-recombination (HR) repair by downregulating BRCA1, RAD51, and RPA32, creating a state of HR deficiency that sensitizes PDAC cells to poly(ADP-ribose) polymerase (PARP) inhibition. Combined MRTX1133 and olaparib treatment produced synergistic cytotoxicity in vitro and durable tumor regression in vivo, even in MRTX1133-resistant models, and remodeled the tumor immune microenvironment with enhanced CD8<sup>+</sup> T-cell infiltration. These findings demonstrate that co-targeting KRAS<sup>G12D</sup> and PARP exploits an induced DNA-repair vulnerability to achieve synthetic lethality and immune activation in KRAS<sup>G12D</sup>-driven PDAC.</p>

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Combination of PARP and KRASG12D inhibitors enhances therapeutic efficacy by exploiting vulnerabilities in PDAC

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月24日

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  • Xin Xu,
  • Xin Chen,
  • Rongli Xu,
  • Zhenyu Huo,
  • Changying Li,
  • Somaira Nowsheen,
  • Khaled Aziz,
  • Fan Yao,
  • Zhenkun Lou,
  • Min Deng

摘要

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy driven predominantly by KRAS mutations, with KRASG12D present in ~40 % of cases. Although the selective KRASG12D inhibitor MRTX1133 shows promising activity, monotherapy responses are incomplete and resistance emerges rapidly. In this study, we show that KRASG12D blockade suppresses homologous-recombination (HR) repair by downregulating BRCA1, RAD51, and RPA32, creating a state of HR deficiency that sensitizes PDAC cells to poly(ADP-ribose) polymerase (PARP) inhibition. Combined MRTX1133 and olaparib treatment produced synergistic cytotoxicity in vitro and durable tumor regression in vivo, even in MRTX1133-resistant models, and remodeled the tumor immune microenvironment with enhanced CD8+ T-cell infiltration. These findings demonstrate that co-targeting KRASG12D and PARP exploits an induced DNA-repair vulnerability to achieve synthetic lethality and immune activation in KRASG12D-driven PDAC.