Most metastatic GIST patients experience progression when treated with tyrosine kinase inhibitors. There is a medical need to achieve more durable therapeutic responses. This can be accomplished by revealing the underlying mechanisms of drug resistance in light of the complexity of the tumour.
We aim to reveal the mechanisms that GIST cells use to escape the imatinib treatment, and thus improve the treatment of advanced GISTs. We also aim to provide better stratification of high-risk patients. This will be addressed through several project.
- Characterize how the transcriptional heterogeneity changes during the development of imatinib resistance, and reveal the molecular determinants causing imatinib resistance. Study set-up using cell lines, xenografts and patient samples.
- Determine if treatment resistance arises from de novo events or from a Darwinian adaptation of pre-existing resistant clones.
- Identify novel vulnerabilities of GIST cells under imatinib selection through CRISPR-Cas9 knockout screening.