Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model

• Published in: British journal of cancer 2013-08, Vol.109 (3), p.667-675
• Main Authors: Arcaroli, J J, Quackenbush, K S, Purkey, A, Powell, R W, Pitts, T M, Bagby, S, Tan, A C, Cross, B, McPhillips, K, Song, E-K, Tai, W M, Winn, R A, Bikkavilli, K, VanScoyk, M, Eckhardt, S G, Messersmith, W A
• Format: Article
• Language: English
• Subjects: 631/154/436; 631/67/1059/99; 631/67/1504/1885; 631/80/86; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adult; Aged; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Growth Processes - drug effects; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Drug Resistance; Enzyme Inhibitors - pharmacology; Epidemiology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Knockdown Techniques; HCT116 Cells; Humans; Medical sciences; Mice; Mice, Nude; Middle Aged; Molecular Medicine; Oncology; Random Allocation; Receptors, Notch - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tetrahydronaphthalenes - pharmacology; Translational Therapeutics; Tumors; Valine - analogs & derivatives; Valine - pharmacology; Wnt Signaling Pathway - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.361

Background: Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ -secretase inhibitor (GSI) PF-03084014. Methods: A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPj κ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting. Results: We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active β -catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours. Conclusion: This study provides evidence that inhibition of γ -secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.