Combination of PARP and KRAS^G12D inhibitors enhances therapeutic efficacy by exploiting vulnerabilities in PDAC

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer driven by KRAS mutations, particularly KRAS^G12D.
• Selective KRAS^G12D inhibition shows activity but faces incomplete responses and rapid resistance.
• Understanding resistance mechanisms is crucial for effective PDAC treatment.

Purpose of the Study:

• To investigate the effects of KRAS^G12D blockade on DNA repair pathways in PDAC.
• To evaluate the efficacy of combining KRAS^G12D inhibition with PARP inhibition in PDAC.
• To assess the impact of combination therapy on the tumor immune microenvironment.

Main Methods:

• Utilized KRAS^G12D inhibitor MRTX1133 and PARP inhibitor olaparib.
• Assessed homologous-recombination (HR) repair pathway components (BRCA1, RAD51, RPA32).
• Performed in vitro cytotoxicity assays and in vivo tumor regression studies.
• Analyzed changes in the tumor immune microenvironment, including CD8⁺ T-cell infiltration.

Main Results:

• KRAS^G12D blockade with MRTX1133 downregulated key HR repair proteins, inducing HR deficiency.
• Combined MRTX1133 and olaparib demonstrated synergistic cytotoxicity in vitro.
• Combination therapy led to durable tumor regression in vivo, overcoming resistance to MRTX1133 monotherapy.
• Treatment remodeled the tumor microenvironment, increasing CD8⁺ T-cell infiltration.

Conclusions:

• Co-targeting KRAS^G12D and PARP exploits induced DNA repair vulnerabilities for synthetic lethality in PDAC.
• Combination therapy offers a promising strategy for overcoming KRAS^G12D-driven PDAC and enhancing anti-tumor immunity.
• This approach may be effective even in tumors resistant to KRAS^G12D inhibition alone.