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

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

Research output: Contribution to journalArticle

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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 tothe IC50 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 shRNAknockdownstudies. Baseline gene array data fromCRC 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.

Original languageEnglish
Pages (from-to)3351-3362
Number of pages12
JournalMolecular Cancer Therapeutics
Volume9
Issue number12
DOIs
Publication statusPublished - 2010 Dec 1
Externally publishedYes

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Colorectal Neoplasms
Cell Line
Wnt Signaling Pathway
Heterografts
Genes
Critical Pathways
AZD 6244
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Immunoblotting
Inhibitory Concentration 50
Up-Regulation
Biomarkers
Clinical Trials
Mutation
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tentler, J. J., Nallapareddy, S., Tan, A-C., Spreafico, A., Pitts, T. M., Morelli, M. P., ... Eckhardt, S. G. (2010). Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-Mutated colorectal cancer. Molecular Cancer Therapeutics, 9(12), 3351-3362. https://doi.org/10.1158/1535-7163.MCT-10-0376

Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-Mutated colorectal cancer. / Tentler, John J.; Nallapareddy, Sujatha; Tan, Aik-Choon; Spreafico, Anna; Pitts, Todd M.; Morelli, M. Pia; Selby, Heather M.; Kachaeva, Maria I.; Flanigan, Sara A.; Kulikowski, Gillian N.; Leong, Stephen; Arcaroli, John J.; Messersmith, Wells A.; Eckhardt, S. Gail.

In: Molecular Cancer Therapeutics, Vol. 9, No. 12, 01.12.2010, p. 3351-3362.

Research output: Contribution to journalArticle

Tentler, JJ, Nallapareddy, S, Tan, A-C, Spreafico, A, Pitts, TM, Morelli, MP, Selby, HM, Kachaeva, MI, Flanigan, SA, Kulikowski, GN, Leong, S, Arcaroli, JJ, Messersmith, WA & Eckhardt, SG 2010, 'Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-Mutated colorectal cancer', Molecular Cancer Therapeutics, vol. 9, no. 12, pp. 3351-3362. https://doi.org/10.1158/1535-7163.MCT-10-0376
Tentler, John J. ; Nallapareddy, Sujatha ; Tan, Aik-Choon ; Spreafico, Anna ; Pitts, Todd M. ; Morelli, M. Pia ; Selby, Heather M. ; Kachaeva, Maria I. ; Flanigan, Sara A. ; Kulikowski, Gillian N. ; Leong, Stephen ; Arcaroli, John J. ; Messersmith, Wells A. ; Eckhardt, S. Gail. / Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-Mutated colorectal cancer. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 12. pp. 3351-3362.
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