Work

Kinomic profiling identifies focal adhesion kinase 1 as a therapeutic target in advanced clear cell renal cell carcinoma

Year: 2017

Type: article

Abstract: // Arindam P. Ghosh 5, * , Christopher D. Willey 1, * , Joshua C. Anderson 1 , Karim Welaya 1 , Dongquan Chen 2 , Amitkumar Mehta 3 , Pooja Ghatalia 4 , Ankit Madan 3 , Gurudatta Naik 3 , Sunil Sudarshan 5, 6 , Guru Sonpavde 3 1 Department of Radiation Oncology, University of Alabama Birmingham (UAB) Medical Center, Birmingham, Alabama, USA 2 Department of Biostatistics, UAB Medical Center, Birmingham, Alabama, USA 3 Department of Medicine, Section of Hematology-Oncology, UAB Medical Center, Birmingham, Alabama, USA 4 Department of Medicine, UAB Medical Center, Birmingham, Alabama, USA 5 Department of Urology, UAB Medical Center, Birmingham, Alabama, USA 6 Birmingham VA Medical Center, Birmingham, Alabama, USA * These authors have contributed equally to this work Correspondence to: Guru Sonpavde, email: [email protected] Sunil Sudarshan, email: [email protected] Keywords: clear cell renal cell carcinoma, kinomics, focal adhesion kinase, metastasis, therapeutic validation Received: November 17, 2016 Accepted: February 07, 2017 Published: March 18, 2017 ABSTRACT The introduction of targeted therapies has caused a paradigm shift in the treatment of metastatic clear cell (cc)-renal cell carcinoma (RCC). We hypothesized that determining differential kinase activity between primary and metastatic tumor sites may identify critical drivers of progression and relevant therapeutic targets in metastatic disease. Kinomic profiling was performed on primary tumor and metastatic tumor deposits utilizing a peptide substrate microarray to detect relative tyrosine phosphorylation activity. Pharmacologic and genetic loss of function experiments were used to assess the biologic significance of the top scoring kinase on in vitro and in vivo tumor phenotypes. Kinomics identified 7 peptides with increased tyrosine phosphorylation in metastases that were significantly altered (p<0.005). Based on these peptides, bioinformatics analyses identified several candidate kinases activated in metastases compared to primary tumors. The highest ranked upstream kinase was Focal Adhesion Kinase 1 (FAK1). RCC lines demonstrate evidence of elevated FAK1 activation relative to non-transformed renal epithelial cells. Pharmacologic inhibition of FAK1 with GSK2256098 suppresses in vitro tumor phenotypes. In turn, FAK1 knockdown in RCC cells suppresses both in vitro phenotypes and in vivo tumor growth. Collectively, these data demonstrate functional activation of FAK1 in metastases and provide preclinical rationale for targeting this kinase in the setting of advanced ccRCC.

Source: Oncotarget

DOI: 10.18632/oncotarget.16352