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|Ref Type||Journal Article|
|Authors||Kirouac DC, Schaefer G, Chan J, Merchant M, Orr C, Huang SA, Moffat J, Liu L, Gadkar K, Ramanujan S|
|Title||Clinical responses to ERK inhibition in BRAFV600E-mutant colorectal cancer predicted using a computational model.|
|Journal||NPJ systems biology and applications|
|Abstract Text||Approximately 10% of colorectal cancers harbor BRAFV600E mutations, which constitutively activate the MAPK signaling pathway. We sought to determine whether ERK inhibitor (GDC-0994)-containing regimens may be of clinical benefit to these patients based on data from in vitro (cell line) and in vivo (cell- and patient-derived xenograft) studies of cetuximab (EGFR), vemurafenib (BRAF), cobimetinib (MEK), and GDC-0994 (ERK) combinations. Preclinical data was used to develop a mechanism-based computational model linking cell surface receptor (EGFR) activation, the MAPK signaling pathway, and tumor growth. Clinical predictions of anti-tumor activity were enabled by the use of tumor response data from three Phase 1 clinical trials testing combinations of EGFR, BRAF, and MEK inhibitors. Simulated responses to GDC-0994 monotherapy (overall response rate = 17%) accurately predicted results from a Phase 1 clinical trial regarding the number of responding patients (2/18) and the distribution of tumor size changes ("waterfall plot"). Prospective simulations were then used to evaluate potential drug combinations and predictive biomarkers for increasing responsiveness to MEK/ERK inhibitors in these patients.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF V600E||colorectal cancer||sensitive||Cobimetinib + Vemurafenib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of Cotellic (cobimetinib) and Zelboraf (vemurafenib) inhibited tumor growth in a cell line xenograft model of colorectal cancer harboring BRAF V600E (PMID: 28649441).||28649441|