Colorectal cancer is one of the most common cancers worldwide, with an estimated 1.2 million cases annually and a mortality of more than 600,000 people each year. Currently, the treatment of cancer, both in its initial phase and in patients with metastases, is based mainly on chemotherapy. It takes, however, predictive biomarkers of response to help identify the group of patients who could benefit from certain chemotherapy treatments, and to avoid unnecessary toxicity in those patients who will not benefit from a particular drug. At the moment, very few predictive biomarkers of response to chemotherapy have been identified, and none of them is used in clinical practice. In this sense, functional genetic screening could be a powerful tool to identify the mechanisms of response to drugs and interactions that can be lethal to tumour cells.
In order to move forward on this path of identification of biomarkers against cancer, two researchers of IDIBELL’s Procure Programme, Drs. Alberto Villanueva and David G. Molleví, together with Dr. Ramon Salazar, Chief of Medical Oncology at ICO, and with the support of the Animal House Service of IDIBELL have actively participated in a study led by Dr. René Bernands and recently published by the prestigious journal Cell, which has been developed in collaboration with various European research centers. The team has been specifically focusing on one of the subsets of patients suffering from colorectal cancer: those with the V600E mutation in the BRAF protein (a kinase of the RAS-RAF-MEK-ERK pathway), representing approximately 10 % of patients for this cancer. Previously, several reports have already shown the negative impact that this mutation has on the prognosis of colorectal cancer and, especially, in the treatment of metastatic cancer.
It is interesting to note that colon cancers with BRAF (V600E) mutation have a characteristic gene expression profile that is also found in some tumours that do not have this mutation. Overall, these tumours are grouped under the name BRAF-like tumours and represent about 20 % of all colon cancers. In these patients, researchers have conducted a genetic study to identify the vulnerabilities of colon cancer cells BRAF-like. In the published work, RANBP2 protein is regarded as essential for the survival of tumour-like factor BRAF, but not for tumour cells from other subgroups of colon cancer. RANBP2 triggers suppression defects leading to mitotic cell death only in BRAF-like tumour cells. Consequently, the published work involving IDIBELL and ICO describes a specific Achilles heel of these cells, which can be treated with vinorelbine, a chemotherapeutic drug that is currently not used clinically for the treatment of colon cancer.
The results published in Cell show the usefulness of functional genetic approaches in describing the vulnerabilities of various subgroups of cancers, an approach susceptible to be explored from the clinical side. In this regard, a clinical phase II trial is being carried out within the MoTriColor project, funded by the European Commission, in order to evaluate the effectiveness of vinorelbine in colorectal cancer patients that are stratified according to their expression profile (BRAF-like).
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