Abstract
The intracytoplasmic tyrosine kinase Src serves both as a conduit and a regulator for multiple processes required for the proliferation and survival cancer cells. In some cancers, Src engages with receptor tyrosine kinases to mediate downstream signaling and in other cancers, it regulates gene expression. Src therefore represents a viable oncologic target. However, clinical responses to Src inhibitors, such as dasatinib have been disappointing to date. We identified Stat3 signaling as a potential bypass mechanism that enables renal cell carcinoma (RCC) cells to escape dasatinib treatment. Combined Src-Stat3 inhibition using dasatinib and CYT387 (a JAK/STAT inhibitor) synergistically reduced cell proliferation and increased apoptosis in RCC cells. Moreover, dasatinib and CYT387 combine to suppress YAP1, a transcriptional co-activator that promotes cell proliferation, survival and organ size. Importantly, this combination was well tolerated, and caused marked tumor inhibition in RCC xenografts. These results suggest that combination therapy with inhibitors of Stat3 signaling may be a useful therapeutic approach to increase the efficacy of Src inhibitors.
Keywords:
STAT3; Src; cancer; kidney; kinase inhibitors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects
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Benzamides / pharmacology*
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Carcinoma, Renal Cell / drug therapy*
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Carcinoma, Renal Cell / enzymology
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dasatinib / pharmacology*
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Dose-Response Relationship, Drug
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Drug Synergism
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Gene Expression Regulation, Neoplastic
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Kidney Neoplasms / drug therapy*
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Kidney Neoplasms / enzymology
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Kidney Neoplasms / genetics
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Kidney Neoplasms / pathology
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Mice
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Molecular Targeted Therapy
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Pyrimidines / pharmacology*
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STAT3 Transcription Factor / antagonists & inhibitors*
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Time Factors
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Transcription Factors
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Transcription, Genetic
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
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YAP-Signaling Proteins
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src-Family Kinases / antagonists & inhibitors*
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src-Family Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Benzamides
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Phosphoproteins
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Protein Kinase Inhibitors
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Pyrimidines
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STAT3 Transcription Factor
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STAT3 protein, human
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Transcription Factors
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YAP-Signaling Proteins
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YAP1 protein, human
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N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
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src-Family Kinases
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Dasatinib