Enhancing KRAS inhibition in Pancreatic Ductal Adenocarcinoma through a small molecule-based combination screening

• Grant number: 25/12623-0
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: November 01, 2025
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Pedro Luiz Porfirio Xavier
• Grantee: Raphael Lucas More
• Supervisor: Susanne Muller-Knapp
• Host Institution: Faculdade de Zootecnia e Engenharia de Alimentos (FZEA). Universidade de São Paulo (USP). Pirassununga , SP, Brazil
• Institution abroad: Goethe University Frankfurt, Germany
• Associated to the scholarship: 24/06143-2 - Establishment of a high-content screening platform in 3D in vitro models to screen and identify potential therapeutic targets for PDAC, BP.MS

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is considered one of the most aggressive and lethal cancers, with a high capacity for metastasis and relatively poor patient survival rates. Moreover, several challenges arise due to difficulties in early diagnosis, the complex pathophysiology of the disease, and the limited therapeutic possibilities. Mutational activation of the KRAS oncogene is found in more than 90% of cases and plays a key role in the PDAC initiation and progression. Thus, the development of KRAS inhibitors such as MRTX1133, BI-2865, and ACB13 represented a breakthrough for PDAC treatment. However, resistance mechanisms to KRAS inhibition remain a major challenge and require further investigation. In this context, this BEPE project aims to identify targets that synergize with KRAS inhibition in a resistant tumor-stroma spheroid model. To identify promising targets, a High Content Screening will be performed using a compound library, including protein kinase inhibitors, epigenetic proteins, G protein-coupled receptors, membrane solute transporters, and Proteolysis Targeting Chimera (PROTAC), in combination with the KRASG12D inhibitor MRTX1133. By applying a compound screening and compound synergy assay, we aim to identify effective synergistic compounds for the development of novel strategies to overcome KRAS resistance. (AU)