Drug Sensitivity Screening and Targeted Pathway Analysis Reveal a Multi-Driver Proliferative Mechanism and Suggest a Strategy of Combination Targeted Therapy for Colorectal Cancer Cells.

Abstract

Treatment of colorectal cancer mostly relies on traditional therapeutic approaches, such as surgery and chemotherapy. Limited options of targeted therapy for colorectal cancer narrowly focus on blocking cancer-generic targets VEGFR and EGFR. Identifying the oncogenic drivers, understanding their contribution to proliferation, and finding inhibitors to block such drivers are the keys to developing targeted therapy for colorectal cancer. In this study, ten colorectal cancer cell lines were screened against a panel of protein kinase inhibitors blocking key oncogenic signaling pathways. The results show that four of the 10 cell lines did not respond to any kinase inhibitors significantly, the other six were mildly inhibited by AZD-6244, BMS-754807, and/or dasatinib. Mechanistic analyses demonstrate that these inhibitors independently block the MAP kinase pathway, IR/IGF-1R/AKT pathway, and Src kinases, suggesting a multi-driver nature of proliferative signaling in these cells. Most of these cell lines were potently and synergistically inhibited by pair-wise combinations of these drugs. Furthermore, seven of the 10 cell lines were inhibited by the triple combination of AZD-6244/BMS-754807/dasatinib with IC50's between 10 and 84 nM. These results suggest that combination targeted therapy may be an effective strategy against colorectal cancer.

• Authors: Jinyan Shen, Li Li, Tao Yang, Niuliang Cheng, Gongqin Sun
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 24 Issue 3 (Feb 11 2019) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 30754629 (Publication Type: Journal Article)

Chemical References

• AZD 6244
• BMS 754807
• Benzimidazoles
• IGF1R protein, human
• Phosphoproteins
• Pyrazoles
• Receptors, Somatomedin
• SKAP1 protein, human
• Triazines
• Receptor, IGF Type 1
• Receptor, Insulin
• Proto-Oncogene Proteins c-akt
• Dasatinib

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Benzimidazoles (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colorectal Neoplasms (drug therapy, metabolism)
• Dasatinib (pharmacology)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Gene Regulatory Networks (drug effects)
• HCT116 Cells
• Humans
• MAP Kinase Signaling System (drug effects)
• Molecular Targeted Therapy
• Phosphoproteins (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrazoles (pharmacology)
• Receptor, IGF Type 1
• Receptor, Insulin (metabolism)
• Receptors, Somatomedin (metabolism)
• Signal Transduction (drug effects)
• Triazines (pharmacology)