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KRASgetaway: a preclinical investigation for control of the KRAS oncogene

Grant number: 23/02032-9
Support Opportunities:Regular Research Grants
Duration: September 01, 2023 - August 31, 2025
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Renato José da Silva Oliveira
Grantee:Renato José da Silva Oliveira
Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil
Associated researchers: Ana Carolina Laus ; Josiane Mourão Dias ; Letícia Ferro Leal ; Olga Catarina Lopes Martinho ; Rui Manuel Vieira Reis ; Silvia Aparecida Teixeira

Abstract

Gain-of-function mutations in the KRAS gene lead to constitutive protein activity, which is associated with tumorigenesis and tumor progression in pancreatic, colorectal, and lung cancer. The challenge in creating therapies against KRAS has extended for decades due to the structural complexity of this protein. However, after the discovery of druggable portions in some of the KRAS variants, it became possible to design inhibitors with improved potency, selectivity, and bioavailability such as Sotorasib for the G12C variant, and MRTX1133 for the G12D variant. However, the molecular mechanisms involved in resistance and failure represent the greatest current challenge for this treatment and need to be understood. The objective of the project is to preclinically investigate the molecular alterations that lead to failure in response to approved (anti-KRAS G12C) and late-stage approved (anti-KRAS G12D) KRAS therapies, seeking a therapeutic solution for acquired resistance to these inhibitors. The project will be divided into three stages: (1) Creation of resistance models to KRAS inhibitors; (2) Search for markers of resistance to anti-KRAS therapies; and (3) Evaluation of therapeutic combinations capable of restoring sensitivity to KRAS inhibitors. A total of 4 mutant KRAS tumor cell lines (G12C or G12D) will be continuously exposed to KRAS inhibitors (Sotorasib and MRTX1133) to create resistant clones, where molecular changes in the expression profile of genes related to proliferation and immune response pathways will be evaluated by the NanoString platform. Additionally, differential protein expression of resistant clones relative to sensitive ones will be evaluated by protein arrays of KRAS-mediated signaling pathways and immune response protein. In vitro molecular findings will be validated in tumor samples from patient's refractory to anti-KRAS therapy treated at this institution. Therapeutic combinations will be proposed to control resistance to KRAS inhibitors, evaluated through cellular assays of proliferation, invasion, migration, colony formation, analysis of cell cycle and cell death in 2D and 3D cellular models, and xenograft models. We hope that this preclinical investigation platform can identify biomarkers related to anti-KRAS therapy failure and demonstrate the best therapeutic combinations to control the KRAS oncogene in patients still without treatment prospects, after progression disease. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
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