Work

Src and STAT3 inhibitors synergize to promote tumor inhibition in renal cell carcinoma

Year: 2015

Type: article

Abstract: // Hui-Wen Lue 1, * , Brook Cole 1, * , Soumya A. M. Rao 1 , Jennifer Podolak 1 , Ahna Van Gaest 1 , Carly King 2 , Christopher A. Eide 3, 4 , Beth Wilmot 5 , Changhui Xue 1 , Paul T. Spellman 6 , Laura M. Heiser 2 , Jeffrey W. Tyner 3, 7 , George V. Thomas 1, 8 1 OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA 2 Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239, USA 3 Hematology and Oncology, Oregon Health and Science University, Portland, OR 97239, USA 4 Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR 97239, USA 5 Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, OR 97239, USA 6 Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA 7 Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR 97239, USA 8 Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR 97239, USA * These authors have contributed equally to this work Correspondence to: George V. Thomas, e-mail: [email protected] Keywords: cancer, kinase inhibitors, kidney, Src, STAT3 Received: June 22, 2015 Accepted: October 04, 2015 Published: November 26, 2015 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.5971