title: Src and STAT3 inhibitors synergize to promote tumor inhibition in renal cell carcinoma.
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.
authors.affiliation: OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Lue
authors.affiliation: OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Brook
authors.initials: B
authors.lastname: Cole
authors.affiliation: OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Soumya A M
authors.initials: SA
authors.lastname: Rao
authors.affiliation: OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Podolak
authors.affiliation: OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Ahna
authors.initials: A
authors.lastname: Van Gaest
authors.affiliation: Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Carly
authors.initials: C
authors.lastname: King
authors.affiliation: Hematology and Oncology, Oregon Health and Science University, Portland, OR 97239, USA.|Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.affiliation: Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Wilmot
authors.affiliation: OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Changhui
authors.initials: C
authors.lastname: Xue
authors.affiliation: Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.affiliation: Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Heiser
authors.affiliation: Hematology and Oncology, Oregon Health and Science University, Portland, OR 97239, USA.|Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.|Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: George V
authors.initials: GV
authors.lastname: Thomas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; D019061:src-Family Kinases; D000069439:Dasatinib
keywords: STAT3; Src; cancer; kidney; kinase inhibitors