Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma

• Published in: Blood 2015-12, Vol.126 (26), p.2821-2831
• Main Authors: Dai, Lu, Trillo-Tinoco, Jimena, Cao, Yueyu, Bonstaff, Karlie, Doyle, Lisa, Del Valle, Luis, Whitby, Denise, Parsons, Chris, Reiss, Krzysztof, Zabaleta, Jovanny, Qin, Zhiqiang
• Format: Article
• Language: English
• Subjects: Adult; Animals; Apoptosis - drug effects; Cell Cycle Checkpoints - drug effects; Comet Assay; Crizotinib; DNA Damage - drug effects; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Hepatocyte Growth Factor - antagonists & inhibitors; Herpesviridae Infections - complications; Herpesvirus 8, Human; Humans; Immunoblotting; Immunocompromised Host; Lymphoid Neoplasia; Lymphoma, Primary Effusion - immunology; Lymphoma, Primary Effusion - pathology; Male; Mice; Mice, SCID; Middle Aged; Oligonucleotide Array Sequence Analysis; Piperidines - pharmacology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Pyrazoles; Pyridines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; Xenograft Model Antitumor Assays; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2015-07-658823

Kaposi sarcoma–associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL) with a poor prognosis in immunocompromised patients. However, it still lacks effective treatment which urgently requires the identification of novel therapeutic targets for PEL. Here, we report that the hepatocyte growth factor (HGF)/c-MET pathway is highly activated by KSHV in vitro and in vivo. The selective c-MET inhibitor, PF-2341066, can induce PEL apoptosis through cell cycle arrest and DNA damage, and suppress tumor progression in a xenograft murine model. By using microarray analysis, we identify many novel genes that are potentially controlled by HGF/c-MET within PEL cells. One of the downstream candidates, ribonucleoside-diphosphate reductase subunit M2 (RRM2), also displays the promising therapeutic value for PEL treatment. Our findings provide the framework for development of HGF/c-MET–focused therapy and implementation of clinical trials for PEL patients. •The HGF/c-MET pathway has a complex network to control KSHV+ PEL cell survival.•The c-MET inhibitor induces PEL apoptosis and suppresses tumor progression in vivo.