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Molecules 2019, 24(3), 623; https://doi.org/10.3390/molecules24030623

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

1,2
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2,3
,
1,2
,
1,* and 1,2,*
1
Department of Biochemistry and Molecular Biology; Shanxi Medical University, Taiyuan 030001, Shanxi, China
2
Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA
3
Department of Cell Biology and Medical Genetics, Shanxi Medical University, Taiyuan 030001, Shanxi, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Christian Peifer
Received: 15 January 2019 / Revised: 1 February 2019 / Accepted: 7 February 2019 / Published: 11 February 2019
(This article belongs to the Special Issue Kinase Inhibitors II)
Full-Text   |   PDF [3208 KB, uploaded 11 February 2019]   |  

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. View Full-Text
Keywords: colorectal cancer; combination therapy; dose reduction index; protein kinase inhibitors; targeted therapy colorectal cancer; combination therapy; dose reduction index; protein kinase inhibitors; targeted therapy
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Shen, J.; Li, L.; Yang, T.; Cheng, N.; Sun, G. 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. Molecules 2019, 24, 623.

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