Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer

Muscle-invasive urothelial carcinoma (UC) is treated with cisplatin-based chemotherapy, which is only moderately efficient, mostly due to development of resistance. New therapy approaches are therefore urgently needed. Epigenetic alterations due to frequent mutations in epigenetic regulators contribute to development of the disease and to treatment resistance, and provide targets for novel drug combination therapies. Here, we determined the cytotoxic impact of the second-generation bromodomain protein inhibitor (BETi) PLX51107 on UC cell lines (UCC) and normal HBLAK control cells. PLX51107 inhibited proliferation, induced apoptosis, and acted synergistically with the histone deacetylase inhibitor romidepsin. While PLX51107 caused significant DNA damage, DNA damage signaling and DNA repair were impeded, a state defined as BRCAness. Accordingly, the drug strongly synergized with cisplatin more efficiently than romidepsin, and with the PARP inhibitor talazoparib to inhibit proliferation and induce cell death in UCC. Thus, a BETi can be used to “episensitize” UC cells to cytotoxic chemotherapy and inhibitors of DNA repair by inducing BRCAness in non BRCA1/2 mutated cancers. In clinical applications, the synergy between PLX51107 and other drugs should permit significant dosage reductions to minimize effects on normal tissues.

Section: Discussionmentioning

confidence: 99%

Epigenetic Treatment of Urothelial Carcinoma Cells Sensitizes to Cisplatin Chemotherapy and PARP Inhibitor Treatment

Thy

Hommel

Meneceur

et al. 2021

“…Other inhibitors are currently tested in combination with PARPi (ClinicalTrials.gov Identifier: NCT03057145). Epigenetic resensitization through DNA methyltransferase (DNMT) inhibitors could be a synergistic pathway in combination with PARPi since DNMT treatment may induce the BRCAness phenotype [ 79 , 80 ].…”

Section: Discussionmentioning

confidence: 99%

Front-Line Maintenance Therapy in Advanced Ovarian Cancer—Current Advances and Perspectives

Reverdy

Sajous

Péron

et al. 2020

Ovarian tumor is the gynecological cancer associated with the highest mortality. Most diseases are diagnosed at an advanced stage, which impairs the chances of prolonged complete remission. The standard front-line treatment of advanced stages combines surgery in an expert center with platinum-based chemotherapy. Most patients experience a relapse in the years following the initial treatment. During the last decade, anti-angiogenic agents used in the maintenance setting improved progression free survival (PFS) over chemotherapy alone. More recently, PARP inhibitors demonstrated substantial efficacy, mainly in patients with germinal or somatic BRCA mutations or other homologous recombination deficiencies (HRD), all involved in double strand DNA Damage Repair (DDR). Other therapeutic paradigms are currently being explored, including combinations of immune-checkpoints inhibitors, chemotherapy, bevacizumab and PARP inhibitors. In addition to these clinical advances, molecular characterization of the tumors and their correlations with drugs efficacy are needed to better understand which patient will benefit the most from the various treatments available to date.

“…In its function as a transcription factor, FOXM1 appears to alter the expression of target genes involved in homologous recombination (HR) in DNA repair such as BRCA1/2 and RAD51 [ 28 , 29 , 30 , 31 ]. In this context, chemotherapeutics targeting DNA are known to trigger DNA damage repair mechanisms (e.g., HR in tumor cells) which may represent a mechanism of resistance [ 32 , 33 , 34 ]. Also, FOXM1 is suspected to be upregulated by olaparib which inversely correlates with sensitivity to the PARP inhibitor [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

FOXM1 Inhibition in Ovarian Cancer Tissue Cultures Affects Individual Treatment Susceptibility Ex Vivo

Brückner

Reinshagen

Hoang

et al. 2021

Diagnosis in an advanced state is a major hallmark of ovarian cancer and recurrence after first line treatment is common. With upcoming novel therapies, tumor markers that support patient stratification are urgently needed to prevent ineffective therapy. Therefore, the transcription factor FOXM1 is a promising target in ovarian cancer as it is frequently overexpressed and associated with poor prognosis. In this study, fresh tissue specimens of 10 ovarian cancers were collected to investigate tissue cultures in their ability to predict individual treatment susceptibility and to identify the benefit of FOXM1 inhibition. FOXM1 inhibition was induced by thiostrepton (3 µM). Carboplatin (0.2, 2 and 20 µM) and olaparib (10 µM) were applied and tumor susceptibility was analyzed by tumor cell proliferation and apoptosis in immunofluorescence microscopy. Resistance mechanisms were investigated by determining the gene expression of FOXM1 and its targets BRCA1/2 and RAD51. Ovarian cancer tissue was successfully maintained for up to 14 days ex vivo, preserving morphological characteristics of the native specimen. Thiostrepton downregulated FOXM1 expression in tissue culture. Individual responses were observed after combined treatment with carboplatin or olaparib. Thus, we successfully implemented a complex tissue culture model to ovarian cancer and showed potential benefit of combined FOXM1 inhibition.