Failure of Iniparib to Inhibit Poly(ADP-Ribose) Polymerase In Vitro

Abstract

Purpose Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination- (HR-) deficient tumors and ability to enhance the action of certain DNA damaging agents. Compared to other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were performed to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib. Experimental design The abilities of iniparib, olaparib and veliparib to i) selectively induce apoptosis or inhibit colony formation in HR-deficient cell lines, ii) selectively sensitize HR-proficient cells to topoisomerase I poisons and iii) inhibit formation of poly(ADP-ribose) polymer in intact cells were compared. Results Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier-generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons campto-thecin and topotecan. Finally, olaparib and veliparib inhibited formation of poly(ADP-ribose) polymer in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit poly(ADP-ribose) polymer formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine or paclitaxel. Conclusions While iniparib kills normal and neoplastic cells at high (>40 µM) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.

Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET

“…However, these results could not be reproduced in a phase III trial, raising questions about the future of PARP inhibition as a therapeutic strategy. Remarkably, in striking analogy with tivantinib, subsequent studies showed that iniparib is not a PARP inhibitor but a cytotoxic agent that kills tumor cells by an unrelated molecular mechanism (37,38). In the iniparib as in the tivantinib case, more rigorous preclinical analysis would have addressed these drugs toward a more appropriate clinical testing, preventing failure, and misinterpretation of clinical trials (39).…”

Breast Cancer Intra-Tumor Heterogeneity: One Tumor, Different Entities

“…Poly adenosine-diphosphate [ADP]-ribose polymerases (PARP) inhibitors have also shown their usefulness against cancer cells with defects in DNA repair machinery. In this context and based on the similarities between BRCA1-mutated breast cancers and basal-like phenotype, PARP inhibitors were tested in patients with triple-negative sporadic breast cancers with controversial results 128 . Nevertheless, this supports BRCA1 methylation testing as a good epigenetic marker of response to PARP inhibitors and to other DNA damage drugs, such as platinum-based agents, as well as cisplatin.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…262 Notably, recent experimental evidence has thrown doubt on the efficacy of Iniparib as a PARP inhibitor. 263 Although PARP may interact with multiple processes involved in DNA damage response 264 and experimental evidence suggested PARP inhibitors may enhance cytotoxic efficacy of different cytotoxic compounds including temozolamide in different models, 265 as for today the jury is still out regarding whether PARP inhibition may have any place in the clinic for tumours wild type for BRCA1/2 except for high-grade ovarian cancers. Immunohistochemical studies have reported reduced 266 as well as elevated 267 PARP expression in triple-negative compared with other types of breast cancers; interestingly, the second study 267 linked elevated PARP levels to improved effect of anthracyclinetaxane combined chemotherapy…”