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

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.

USP7 inhibitors, downregulating CCDC6, sensitize lung neuroendocrine cancer cells to PARP-inhibitor drugs

“…Moreover, in a wide group of SCLC cell lines, the association of veliparib and platinum salt has been reported to improve platinum sensitivity [29].…”

“…Among several approaches of different treatment, the PARP inhibitor veliparib showed limited single agent activity in a panel of SCLC cell lines [29]. However, veliparib was able to potentiate chemotherapy and radiation in vitro and in vivo SCLC cells, in combinatorial assays [29].…”

“…However, veliparib was able to potentiate chemotherapy and radiation in vitro and in vivo SCLC cells, in combinatorial assays [29].…”

Randomized, Placebo-Controlled, Phase II Study of Veliparib in Combination with Carboplatin and Paclitaxel for Advanced/Metastatic Non–Small Cell Lung Cancer

“…This indicates that the responses are "deeper" with the addition of veliparib to platinum-based chemotherapy. Indeed, preclinical studies have demonstrated this phenomenon of PARP inhibition being synergistic with platinum compounds in platinum-sensitive cell lines, but not in refractory cells (19,20). This observation calls for identification of biomarkers to determine platinum sensitivity to identify patients likely to benefit from PARP inhibition.…”

A phase 1 safety study of veliparib combined with cisplatin and etoposide in extensive stage small cell lung cancer: A trial of the ECOG–ACRIN Cancer Research Group (E2511)

“…Limited experience in early phase studies also suggests modest single agent efficacy of a PARP inhibitor in previously treated SCLC patients [10]. We previously showed in in vitro and in vivo models of SCLC that veliparib has limited activity as a single agent but significantly potentiated the cytotoxicity of standard chemotherapy agents currently employed in the clinic to treat SCLC including cisplatin, carboplatin and etoposide[11]. …”