Project no. 2018-01 3900

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related deaths in the world. Owing to the improvements in systemic chemotherapy, targeted therapies and surgical techniques, the survival of patients with metastatic CRC (mCRC) has improved over the past two decades. Still, these therapeutic advances have not brought benefits to all molecular subtypes of CRC. This particularly holds true for the population of mCRC patients with BRAFV600E mutation (7–10%) which have a poor response to most systemic therapies and a very poor prognosis. Vemurafenib, a protein kinase inhibitor of BRAFV600E approved by the FDA for the treatment of metastatic melanoma with BRAFV600E mutation, has raised hopes of treatment for BRAF-mutant CRC. However, opposite to the results seen in patients with BRAFV600E mutant melanoma, single-agent vemurafenib exerted limited clinical efficacy in patients with BRAFV600E mutant CRC. In order to improve outcomes in CRC patients with BRAF mutation, there is a critical need to better understand the mechanisms of resistance to BRAF inhibitors. The BRAFCON project strives to give a new perspective on the processes governing acquired resistance to BRAF inhibition by vemurafenib in BRAFV600E mutant colon cancer cells by integrating different layers of molecular information (proteome, glycoproteome, secretome, and sphingolipidome) while taking into account an intricate interplay of molecular signals both, inside and outside of colon cancer cells that influence multiple aspects of cell behavior. Specific scientific objectives of this project are: 1) to identify and validate in vitro novel actionable pathways, biomarkers and targets associated with the development of resistance to BRAF inhibition by vemurafenib in BRAF-mutant colon cancer cells; 2) to investigate the role of bioactive sphingolipids, their metabolism and signaling in acquired resistance to vemurafenib; 3) to investigate the correlation between the BRAF gene status and the regulation of  sphingolipid metabolic pathways; and 4) to identify and validate in vitro novel combinatorial strategy to counter therapeutic resistance to vemurafenib. Findings obtained in BRAFCON are expected to advance treatment and diagnosis of BRAF-mutant colon cancer patients by contributing to the development of 1) new treatment modalities, and 2) novel potential diagnostic biomarkers for predicting resistance to vemurafenib.