Work

High-throughput simultaneous screen and counterscreen identifies homoharringtonine as synthetic lethal with von Hippel-Lindau loss in renal cell carcinoma

Year: 2015

Type: article

Abstract: // Nicholas C. Wolff 1,2,3 , Andrea Pavía-Jiménez 1,2,3 , Vanina T. Tcheuyap 1,2,3 , Shane Alexander 1,2,3 , Mridula Vishwanath 4,6 , Alana Christie 1 , Xian-Jin Xie 1 , Noelle S. Williams 1,4 , Payal Kapur 1,5 , Bruce Posner 4 , Renée M. McKay 1,3 and James Brugarolas 1,2,3 1 Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA 2 Department of Internal Medicine - Hematology-Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA 3 Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA 5 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 6 BioTek Instruments, Winooski, Vermont, USA Correspondence to: James Brugarolas, email: // Keywords : high-content drug screen, omacetaxine mepesuccinate, patiend-derived xenografts, tumorgrafts Received : May 29, 2015 Accepted : June 21, 2015 Published : July 03, 2015 Abstract Renal cell carcinoma (RCC) accounts for 85% of primary renal neoplasms, and is rarely curable when metastatic. Approximately 70% of RCCs are clear-cell type (ccRCC), and in >80% the von Hippel-Lindau ( VHL ) gene is mutated or silenced. We developed a novel, high-content, screening strategy for the identification of small molecules that are synthetic lethal with genes mutated in cancer. In this strategy, the screen and counterscreen are conducted simultaneously by differentially labeling mutant and reconstituted isogenic tumor cell line pairs with different fluorochromes and using a highly sensitive high-throughput imaging-based platform. This approach minimizes confounding factors from sequential screening, and more accurately replicates the in vivo cancer setting where cancer cells are adjacent to normal cells. A screen of ~12,800 small molecules identified homoharringtonine (HHT), an FDA-approved drug for treating chronic myeloid leukemia, as a VHL -synthetic lethal agent in ccRCC. HHT induced apoptosis in VHL- mutant, but not VHL- reconstituted, ccRCC cells, and inhibited tumor growth in 30% of VHL -mutant patient-derived ccRCC tumorgraft lines tested. Building on a novel screening strategy and utilizing a validated RCC tumorgraft model recapitulating the genetics and drug responsiveness of human RCC, these studies identify HHT as a potential therapeutic agent for a subset of VHL -deficient ccRCCs.

Source: Oncotarget

DOI: 10.18632/oncotarget.4773