Poly (ADP) ribose polymerase enzyme inhibitor, veliparib, potentiates chemotherapy and radiation in vitro and in vivo in small cell lung cancer

• Type of Material: Article
• Authors: Taofeek Owonikoko, Emory University; Guojing Zhang, Emory University; Xingming Deng, Emory University; Michael Rossi, Emory University; Jeffrey Switchenko, Emory University; Gregory H. Doho, Emory University; Zhengjia Chen, Emory University; Sungjin Kim, Emory University; Sandy Strychor, University of Pittsburgh Cancer Institute; Susan M. Christner, University of Pittsburgh Cancer Institute; Jan Beumer, University of Pittsburgh Cancer Institute; Chunyang Li, Emory University; Ping Yue, Emory University; Alice Chen, Cancer Therapy Evaluation Program of the National Cancer Institute; Gabriel Sica, Emory University; Suresh Ramalingam, Emory University; Jeanne Kowalski, Emory University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2014-12-01
• Publisher: Wiley Open Access
• Publication Version: Final Published Version
• Copyright Statement: © 2014 The Authors
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1002/cam4.317
• Title of Journal or Parent Work: Cancer Medicine
• ISSN: 2045-7634
• Volume: 3
• Issue: 6
• Start Page: 1579
• End Page: 1594
• Grant/Funding Information: This work was supported by NIH grants (1K23CA164015, P01CA116676, P30CA138292, P30CA47904, and U01CA099168); and Georgia Research Alliance Distinguished Cancer Scientist Award
• Keywords: BMN 673; PARP INHIBITORS; etoposide; THERAPEUTIC TARGETS; Life Sciences & Biomedicine; Carboplatin; OVARIAN-CANCER; cisplatin; CISPLATIN; veliparib (ABT-888); Oncology; POLY(ADP-RIBOSE) POLYMERASE; CHROMATIN TRANSCRIPTION FACT; SCLC; DNA-REPAIR; Science & Technology; DEPENDENT PROTEIN-KINASE; BREAST-CANCER; PARP
• Research Categories: Health Sciences, Oncology; Health Sciences, Radiology

Abstract

Poly (ADP) ribose polymerase (PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer (SCLC). We investigated the therapeutic impact of PARP inhibition in SCLC. In vitro cytotoxicity of veliparib, cisplatin, carboplatin, and etoposide singly and combined was determined by MTS in 9 SCLC cell lines (H69, H128, H146, H526, H187, H209, DMS53, DMS153, and DMS114). Subcutaneous xenografts in athymic nu/nu mice of H146 and H128 cells with relatively high and low platinum sensitivity, respectively, were employed for in vivo testing. Mechanisms of differential sensitivity of SCLC cell lines to PARP inhibition were investigated by comparing protein and gene expression profiles of the platinum sensitive and the less sensitive cell lines. Veliparib showed limited single-agent cytotoxicity but selectively potentiated (≥ 50% reduction in IC50 ) cisplatin, carboplatin, and etoposide in vitro in five of nine SCLC cell lines. Veliparib with cisplatin or etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128 xenografts. The potentiating effect of veliparib was associated with in vitro cell line sensitivity to cisplatin (CC = 0.672; P = 0.048) and DNA-PKcs protein modulation. Gene expression profiling identified differential expression of a 5-gene panel (GLS, UBEC2, HACL1, MSI2, and LOC100129585) in cell lines with relatively greater sensitivity to platinum and veliparib combination. Veliparib potentiates standard cytotoxic agents against SCLC in a cell-specific manner. This potentiation correlates with platinum sensitivity, DNA-PKcs expression and a 5-gene expression profile.