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

Cancer Medicine

Taofeek K. Owonikoko⁴  Guojing Zhang⁴  Xingming Deng⁵  Michael R. Rossi⁷  Jeffrey M. Switchenko⁵  Gregory H. Doho²  Zhengjia Chen⁵  Sungjin Kim⁵  Sandy Strychor⁶  Susan M. Christner⁶  Jan Beumer⁶  Chunyang Li⁵  Ping Yue⁴  Alice Chen³  Gabriel L. Sica¹  Suresh S. Ramalingam⁴  Jeanne Kowalski⁵  Fadlo R. Khuri⁴ 

[1] Department of Pathology, Emory University School of Medicine, Atlanta, Georgia;Emory Integrated Genomics Core Lab, Emory University School of Medicine, Atlanta, Georgia;Investigational Drug Branch, Cancer Therapy Evaluation Program of the National Cancer Institute, Bethesda, Maryland;Department of Hematology & Medical Oncology, Emory University School of Medicine, Atlanta, Georgia;Winship Cancer Institute of Emory University, Atlanta, Georgia;Molecular Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania;Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia

关键词: Carboplatin;    cisplatin;    etoposide;    PARP;    SCLC;    veliparib (ABT‐888);   

DOI  :  10.1002/cam4.317

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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