Resistance to EGFR-targeted therapy in colorectal cancer: biological significance of stromal-derived neuregulin-1

01 January 2013 → 31 December 2015
Research Foundation - Flanders (FWO)
Research disciplines
  • Social sciences
    • Animal experimental and comparative psychology
    • Applied psychology
    • Human experimental psychology
Project description

Anti-EGFR therapy (cetuximab or panitumumab) is a targeted therapy in metastatic colorectal cancer (CRC). The mutation state of K-RAS, a downstream intermediate of HER signalling, is used to predict therapy resistance. Unfortunately only half of the currently treated wild type tumors respond, indicating additional upfront primary resistance mechanisms. Furthermore, initially responding tumors may acquire secondary resistance. Our group recently found that tumor-associated mesenchymal cells stimulate invasion, survival and tumorigenesis of CRC cells through paracrine NRG1-mediated activation of HER2/HER3 dimer (De Boeck et al., Gut, in press; data available upon request). Building on this body of evidence, an integrated approach using cell culture models, biochemical-histopathological analysis and pre-clinical evaluation will allow to find significant insights in stromal-dependent delivery of signalling ligands that are associated with upfront resistance to anti-EGFR therapy or mechanisms of acquired resistance to anti-EGFR therapy. Translational implementation of these findings would have huge impact on the costefficiency model of these drugs and current CRC treatment. Furthermore, targetable mechanisms of acquired resistance would allow potential long lasting remission and cure for some patients.