KRAS^G12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for...

Area of Science:

• Oncology
• Molecular Biology
• Drug Delivery Systems

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited treatment options.
• KRAS^G12D mutations are common drivers in PDAC, and inhibitors like MRTX1133 show promise but face resistance.
• Metabolic reprogramming, particularly the pentose phosphate pathway (PPP), is implicated in cancer progression and drug resistance.

Purpose of the Study:

• To investigate the role of KRAS^G12D in metabolic reprogramming and MRTX1133 resistance in PDAC.
• To identify novel therapeutic targets and strategies to overcome MRTX1133 resistance.
• To develop an enhanced drug delivery system for improved therapeutic efficacy.

Main Methods:

• Analysis of KRAS^G12D-driven metabolic changes, focusing on the pentose phosphate pathway (PPP).
• Investigation of the regulatory axis involving p53, G6PD, Rb/E2F1, and UBE2T.
• Genetic and pharmacological inhibition of UBE2T, and development of a nano co-delivery system using F-127, PGG, and MRTX1133.

Main Results:

• KRAS^G12D promotes a PPP-dominant metabolism, contributing to PDAC progression and MRTX1133 resistance.
• The KRAS^G12D-driven pathway involves p53 degradation and amplified UBE2T transcription.
• Inhibition of UBE2T and the novel nano co-delivery system significantly enhanced therapeutic efficacy, achieving durable remissions and long-term survival in preclinical models.

Conclusions:

• KRAS^G12D-mediated PPP reprogramming is a key mechanism of MRTX1133 resistance in PDAC.
• Targeting UBE2T, in combination with MRTX1133 delivered via a nano system, represents a promising therapeutic strategy for KRAS^G12D-mutated PDAC.
• This study provides a novel approach to overcome drug resistance and improve outcomes for PDAC patients.