Raw immunoblotting images from the article titled "KRAS G12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC"
Description
This data consists of raw immunoblotting images from the article titled "KRAS G12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC". The KRAS-G12D inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. In this article, we indicate that KRAS-G12D remodels pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRAS-G12D drives excessive degradation of p53 and G6PD-mediated PPP reprogramming through Rb/E2F1/p53 axis-regulated feedback loops that amplify UBE2T transcription. Genetic ablation or pharmacological inhibition of UBE2T significantly suppresses PDAC progression and potentiates MRTX1133 efficacy. Leveraging structure advantages of the UBE2T inhibitor PGG, we develop a self-assembling nano co-delivery system with F-127, PGG, and MRTX1133. This system enhances the efficacy of PGG and MRTX1133, achieving durable remissions (85% overall response rate) and long-term survival (100% progression-free survival) in patient-derived xenografts and spontaneous PDAC mice. This study reveals the role of KRAS-G12D-prefered PPP reprogramming in MRTX1133 resistance and propose a potentially therapeutic strategy for KRASG12D-mutated PDAC.