Colorectal cancer (CRC) is heterogeneous both at the clinical and molecular levels, constituting a major challenge for prognosis and treatment.

However, recent efforts aimed at classifying CRC into distinct molecular subtypes (CMS) brought new therapeutic prospects.

The overall goal of this project is to exploit the dependence of the CMS4 subtype to protein quality control systems. Indeed, CMS4 patients do not respond well to standard-of-care treatments but have been proposed to be highly susceptible to HSP90 inhibition.

Here we propose to study and target the RUVBL1 and RUVBL2 chaperones, which are HSP90 cofactors with negative prognostic value and frequently overexpressed in CRC tumours.

These proteins form a hetero-hexameric complex that carries AAA+ ATPase activity and they recently emerged as a novel chaperone for several multimeric complexes involved in cell proliferation.

We will use and further optimize compounds recently characterized as specific inhibitors of RUVBL1/2 ATPase activity, with promising effects in tumor xenograX models.

Using a collection of validated preclinical models, we will determine which CRC subtypes show the greatest sensitivity to RUVBL1/2 inhibi8on, either in monotherapy or in combination with genotoxic or proteotoxic stress.

In parallel, we will iden8fy the molecular determinants of RUVBL1/2 sensitivity. We will characterize the network of clients controlled by RUVBL1/2 and the molecular mechanisms underlying their chaperone activities.

Overall, we expect to show that a strategy combining RUVBL1/2 chaperone inhibition with other proteostasis-disrupting compounds or chemotherapeutic drugs will have a significant therapeutic potential. This project will provide a basis for novel biomarker-guided targeted therapies.