Abstract |
Use of kinase inhibitors in cancer therapy leads invariably to acquired resistance stemming from kinase reprogramming. To overcome the dynamic nature of kinase adaptation, we asked whether a signal-integrating downstream effector might exist that provides a more applicable therapeutic target. In this study, we reported that the transcriptional factor c-Myc functions as a downstream effector to dictate the therapeutic response to c-Met inhibitors in c-Met-addicted cancer and derived resistance. Dissociation of c-Myc from c-Met control, likely overtaken by a variety of reprogrammed kinases, led to acquisition of drug resistance. Notably, c-Myc blockade by RNA interference or pharmacologic inhibition circumvented the acquired resistance to c-Met inhibition. Combining c-Myc blockade and c-Met inhibition in MET-amplified patient-derived xenograft mouse models heightened therapeutic activity. Our findings offer a preclinical proof of concept for the application of c-Myc-blocking agents as a tactic to thwart resistance to kinase inhibitors.
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Authors | Aijun Shen, Lu Wang, Min Huang, Jingya Sun, Yi Chen, Yan-Yan Shen, Xinying Yang, Xin Wang, Jian Ding, Meiyu Geng |
Journal | Cancer research
(Cancer Res)
Vol. 75
Issue 21
Pg. 4548-59
(Nov 01 2015)
ISSN: 1538-7445 [Electronic] United States |
PMID | 26483207
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2015 American Association for Cancer Research. |
Chemical References |
- 6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline
- MYC protein, human
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins c-myc
- Pyridazines
- Quinazolines
- RNA, Small Interfering
- Triazoles
- Proto-Oncogene Proteins c-met
- Gefitinib
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Topics |
- Animals
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cell Survival
(genetics)
- Drug Resistance, Neoplasm
(genetics)
- Gefitinib
- Humans
- Mice, Inbred BALB C
- Mice, Nude
- Molecular Targeted Therapy
- Neoplasms
(drug therapy)
- Protein Kinase Inhibitors
(therapeutic use)
- Proto-Oncogene Proteins c-met
(antagonists & inhibitors, metabolism)
- Proto-Oncogene Proteins c-myc
(antagonists & inhibitors, genetics)
- Pyridazines
(pharmacology)
- Quinazolines
(pharmacology)
- RNA Interference
- RNA, Small Interfering
- Triazoles
(pharmacology)
- Xenograft Model Antitumor Assays
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