Clinical responses to ERK inhibition in BRAFV600E-mutant colorectal cancer predicted using a computational model
Roughly 10% of colorectal cancers harbor BRAFV600E mutations, which constitutively activate the MAPK signaling path. We searched for to find out whether ERK inhibitor (GDC-0994)-that contains regimens might be of clinical help to these patients according to data from in vitro (cell line) as well as in vivo (cell- and patient-derived xenograft) studies of cetuximab (EGFR), vemurafenib (BRAF), cobimetinib (MEK), and GDC-0994 (ERK) combinations. Preclinical data was utilized to build up a mechanism-based computational model linking cell surface receptor (EGFR) activation, the MAPK signaling path, and tumor growth. Clinical predictions of anti-tumor activity were enabled through tumor response data from three Phase 1 numerous studies testing mixtures of EGFR, BRAF, and MEK inhibitors. Simulated responses to GDC-0994 monotherapy (overall response rate = 17%) precisely Ravoxertinib predicted is a result of a Phase 1 medical trial regarding the amount of responding patients (2/18) and also the distribution of tumor size changes (“waterfall plot”). Prospective simulations were then accustomed to evaluate potential drug combinations and predictive biomarkers for growing responsiveness to MEK/ERK inhibitors during these patients.