Novel approach to targeting and degrading oncogenic mutations for cancer treatment

Gonçalo Bernardes.

Fundación del Sector Público Estatal Centro Nacional de Investigaciones Oncológicas Carlos III, Spain.

Cancers driven by mutations in the KRAS protein are difficult to treat. Existing drugs can block the protein temporarily, but they often require high doses and may lose effectiveness as tumours develop resistance. This project aims to overcome these challenges by developing a small-molecule degrader that eliminates the mutant KRAS entirely rather than merely inhibiting it.

Using proximity-induced degradation, the proposed drug specifically marks the mutant KRAS protein with a reactive component that causes local oxidative damage and targets it for destruction. Unlike approaches that recruit the cellular proteasome, this strategy may prove more robust. A team with expertise in targeted protein degradation and medicinal chemistry will develop and test the compound to establish a new degradation-based therapeutic paradigm that could be generalisable to oncogenic proteins beyond KRAS.

If successful, the approach could deliver more effective treatments for aggressive cancers driven by KRAS mutations, such as non-small-cell lung cancer and colorectal cancer. More broadly, it may open new avenues for targeting proteins currently considered “undruggable”, thereby fostering innovation in precision oncology.

• Javier Bonet-Aleta, University of Cambridge, United Kingdom.

• Cong Tang, Fundação GIMM - Gulbenkian Institute for Molecular Medicine, Portugal.

STAGE 1