Preclinical In vivo Evaluation of Efficacy, Pharmacokinetics, and Pharmacodynamics of a Novel MEK1/2 Kinase Inhibitor RO5068760 in Multiple Tumor Models
Open Access
- 1 January 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 9 (1), 134-144
- https://doi.org/10.1158/1535-7163.mct-09-0601
Abstract
Targeting the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway represents a promising anticancer strategy. Recently, we have reported a novel class of potent and selective non–ATP-competitive MEK1/2 inhibitors with a unique structure and mechanism of action. RO5068760 is a representative of this class showing significant efficacy in a broad spectrum of tumors with aberrant mitogen-activated protein kinase pathway activation. To understand the relationship between systemic exposures and target (MEK1/2) inhibition as well as tumor growth inhibition, the current study presents a detailed in vivo characterization of efficacy, pharmacokinetics, and pharmacodynamics of RO5068760 in multiple xenograft tumor models. For inhibition of MEK1/2 as measured by the phosphorylated ERK levels, the estimated EC50s in plasma were 1.36 μmol/L (880 ng/mL) and 3.35 μmol/L (2168 ng/mL) in LOX melanoma and HT-29 colorectal cancer models, respectively. A similar EC50 (1.41 μmol/L or 915 ng/mL) was observed in monkey peripheral blood lymphocytes. To achieve tumor growth inhibition (≥90%), an average plasma drug concentration of 0.65 or 5.23 μmol/L was required in B-RafV600E or K-Ras mutant tumor models, respectively, which were remarkably similar to the IC90 values (0.64 or 4.1 μmol/L) determined in vitro for cellular growth inhibition. With equivalent in vivo systemic exposures, RO5068760 showed superior efficacy in tumors harboring B-RafV600E mutation. The plasma concentration time profiles indicate that constant p-ERK suppression (>50%) may not be required for optimal efficacy, especially in highly responsive tumors. This study may facilitate future clinical trial design in using biochemical markers for early proof of mechanism and in selecting the right patients and optimal dose regimen. Mol Cancer Ther; 9(1); 134–44Keywords
Other Versions
This publication has 18 references indexed in Scilit:
- American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti–Epidermal Growth Factor Receptor Monoclonal Antibody TherapyJournal of Clinical Oncology, 2009
- KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancerMolecular Cancer Therapeutics, 2009
- Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer TherapyCancer Research, 2009
- Genetic Predictors of MEK Dependence in Non–Small Cell Lung CancerCancer Research, 2008
- Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancerThe Lancet Oncology, 2008
- BRAFV600E Mutation Is Associated with Preferential Sensitivity to Mitogen-Activated Protein Kinase Kinase Inhibition in Thyroid Cancer Cell LinesJournal of Clinical Endocrinology & Metabolism, 2008
- Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced CancersJournal of Clinical Oncology, 2008
- BRAF mutation predicts sensitivity to MEK inhibitionNature, 2005
- Targeting RAS signalling pathways in cancer therapyNature Reviews Cancer, 2003
- Mutations of the BRAF gene in human cancerNature, 2002