Research Seminar: Discovery of novel therapeutic approaches for colorectal cancer

Dr. Stephen Whittaker, Division of Cancer Therapeutics, The Institute of Cancer Research, London

Tuesday 22nd November, 1.00 p.m., Stacey Lecture Theatre 1

 

RAF and MEK inhibitors are effective in BRAF-mutant melanoma but not in BRAF-mutant colorectal cancer. To gain additional insights into this difference, we performed a genome-scale, pooled shRNA enhancer screen in a BRAF-mutant, BRAF inhibitor-resistant colorectal cancer cell line exposed to the selective RAF inhibitor PLX4720. We identified multiple genes along the receptor tyrosine kinase (RTK)-mitogen-activated protein kinase (MAPK) signalling axis that, when suppressed, either genetically or pharmacologically, sensitized cells to the selective RAF inhibitor through sustained inhibition of MAPK signalling. Strikingly, CRAF was a key mediator of resistance that could be overcome by the use of pan-RAF inhibitors in combination with a MEK inhibitor. Furthermore, the combination of pan-RAF and MEK inhibitors displayed strong synergy in melanoma and colorectal cancer cell lines with RAS-activating events. Recently, we have utilised pharmacogenomic data to investigate why KRAS-mutant colorectal cancer can display intrinsic resistance to inhibition of MEK, a key KRAS effector. We identified a gene signature associated with resistance, which was prognostic for poor survival in colorectal cancer patients. Pharmacological suppression of these genes resensitised cells to inhibition of MEK and resulted in synergistic effects on the inhibition of proliferation and the induction of apoptosis. Furthermore, in cells cultured to resistance by chronic exposure to a MEK inhibitor, enrichment of the same gene signature was also observed. Again, pharmacological targeting of our candidate resistance signature restored sensitivity to MEK inhibition. Importantly, we further validated our therapeutic approach in patient-derived models. This work provides further insight into potential acquired and intrinsic resistance mechanisms to BRAF and MEK inhibitors and suggests potential therapeutic strategies for clinical investigation.