Clinical responses to ERK inhibitor (GDC-0994) treatment combinations predicted using a Quantitative Systems Pharmacology model of MAPK signaling in BRAF(V600E)-mutant colorectal cancer

An abstract of a study by Kirouac et al on the clinical response to ERK inhibitor (GDC-0994) treatment combinations predicted using a Quantitative Systems Pharmacology model of MAPK signaling in BRAF(V600E)-mutant colorectal cancer is presented. The study involves a mechanism-based computational model, linking cell surface receptor (EGFR) engagement, the MAPK cascade, feedback mechanisms, and tumor growth regulation. Results showed that GDC-0994 treatment was predicted to be the most effective monotherapy, with an estimated 16% ORR, and synergistic activity was predicted for the combination with cobimetinib, increasing to 30% ORR. The study concludes that increasing response rates to MAPK inhibition in BRAF-CRC will necessitate either the use of predictive biomarkers to pre-select patients with increased MAPK-dependence, or combination with agents targeting orthogonal oncogenic pathways or survival mechanisms.