Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer.

Abstract

Mutant K-ras activity leads to the activation of the RAS/RAF/MEK/ERK pathway in approximately 44% of colorectal cancer (CRC) tumors. Accordingly, several inhibitors of the MEK pathway are under clinical evaluation in several malignancies including CRC. The aim of this study was to develop and characterize predictive biomarkers of response to the MEK1/2 inhibitor AZD6244 in CRC in order to maximize the clinical utility of this agent. Twenty-seven human CRC cell lines were exposed to AZD6244 and classified according to the IC(50) value as sensitive (≤ 0.1 μmol/L) or resistant (>1 μmol/L). All cell lines were subjected to immunoblotting for effector proteins, K-ras/BRAF mutation status, and baseline gene array analysis. Further testing was done in cell line xenografts and K-ras mutant CRC human explants models to develop a predictive genomic classifier for AZD6244. The most sensitive and resistant cell lines were subjected to differential gene array and pathway analyses. Members of the Wnt signaling pathway were highly overexpressed in cell lines resistant to AZD6244 and seem to be functionally involved in mediating resistance by shRNA knockdown studies. Baseline gene array data from CRC cell lines and xenografts were used to develop a k-top scoring pair (k-TSP) classifier, which predicted with 71% accuracy which of a test set of patient-derived K-ras mutant CRC explants would respond to AZD6244, providing the basis for a patient-selective clinical trial. These results also indicate that resistance to AZD6244 may be mediated, in part, by the upregulation of the Wnt pathway, suggesting potential rational combination partners for AZD6244 in CRC.

• Authors: John J Tentler, Sujatha Nallapareddy, Aik Choon Tan, Anna Spreafico, Todd M Pitts, M Pia Morelli, Heather M Selby, Maria I Kachaeva, Sara A Flanigan, Gillian N Kulikowski, Stephen Leong, John J Arcaroli, Wells A Messersmith, S Gail Eckhardt
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 12 Pg. 3351-62 (Dec 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20923857 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• AZD 6244
• Antineoplastic Agents
• Benzimidazoles
• Biomarkers, Tumor
• KRAS protein, human
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Mitogen-Activated Protein Kinase Kinases
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Algorithms
• Animals
• Antineoplastic Agents (pharmacology)
• Benzimidazoles (pharmacology)
• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (genetics, pathology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunoblotting
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Mutation (genetics)
• Oligonucleotide Array Sequence Analysis
• Prognosis
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• Reproducibility of Results
• Signal Transduction (drug effects, genetics)
• Treatment Outcome
• Xenograft Model Antitumor Assays
• ras Proteins (genetics)