Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations

Abstract

Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis) show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR). However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi), become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi)). Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG)–a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF) 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors.

Main implications related to the switch to BRCA1/2 tumor testing in ovarian cancer patients: a proposal of a consensus

“…As Mayor et coll published, “beside the identification of small insertion and deletion present in ctDNA , a comprehensive sequencing assay can detect a variety of previously known and unknown genomic alterations, including missense mutations, larger deletions, or rearrangements that could impact response to treatment” [ 36 ]. Novel strategies for treating tumors with acquired resistance to PARPi are in early stages of investigation, such as inhibition of CDK12 or combinations of therapies such as PARPi , vorinostat, and 6-thioguanine [ 37 ].…”

<p>Transcriptomics Analysis of the Tumor-Inhibitory Pathways of 6-Thioguanine in MCF-7 Cells via Silencing DNMT1 Activity</p>

“…23,24 More notably, 6-TG induced an inhibitory effect on the growth of BRCA-defective tumors, similar to a PARP inhibitor, which was induced because of the inability to repair DNA damage. 25,26 Nevertheless, the effect of 6-TG on the most common breast cancer MCF-7 cell line has not been investigated clearly. Consequently, through KEGG enrichment analysis, our data showed that 6-TG treatment mainly upregulated DEGs involved in two biological pathways, apoptosis and the p53 signaling pathway, in MCF-7 cells.…”

BRCA1 reversion mutation acquired after treatment identified by liquid biopsy

“…Novel strategies for treating tumors with acquired resistance to PARPi are in early stages of investigation, such as inhibition of CDK12 (Johnson et al, 2016) or combinations of therapies such as PARPi, vorinostat, and 6-thioguanine (Yalon et al, 2016). …”