Colon cancer: how a protein predicts who will not respond to chemotherapy
The Irccs Candiolo research published in Cancer Discovery was based on tumour organoids and aims to recognise patients unlikely to respond to Folfiri in advance and pave the way for alternative therapeutic strategies
by Livio Trusolino *
3' min read
3' min read
Chemotherapy is the standard treatment for most patients with inoperable metastatic colon cancer, but responses in terms of disease control only occur in about half of the cases, leaving the other half exposed to ineffective therapy and side effects. My laboratory at the Candiolo Institute - Irccs has studied the mechanisms underlying this resistance using tumour organoids, miniature three-dimensional replicas obtained from patient samples.
Focus on Folfiri
.We focused on Folfiri, a chemotherapy treatment that almost all patients receive during the clinical course. The first observation was that susceptible organoids suffered severe DNA damage after exposure to this type of therapy, while in resistant ones the DNA appeared largely intact: a clue suggesting that resistance was linked to a high capacity for repairing lesions to the DNA structure caused by chemotherapy. There are many enzymes that restore DNA integrity after genotoxic damage, so we began the patient - and at times frustrating - work of systematically analysing the activity of these molecules, looking for a candidate that would work particularly well in resistant tumours.
The breakthrough came after months of unsuccessful experiments, when we found that the RAD51 protein was clearly more highly expressed and more active in resistant organoids. The finding was clear, but remained correlative. We then artificially inserted RAD51 into sensitive models, and verified that they became resistant. Finally, we had found a functional marker causally associated with non-response.
