Transforming Growth Factor Beta and Epithelial to Mesenchymal Transition Alter Homologous Recombination Repair Gene Expression and Sensitize BRCA Wild-Type Ovarian Cancer Cells to Olaparib

Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, largely due to metastasis and drug resistant recurrences. Fifteen percent of ovarian tumors carry mutations in BRCA1 or BRCA2, rendering them vulnerable to treatment with PARP inhibitors such as olaparib. Recent studies have shown that TGFβ can induce “BRCAness” in BRCA wild-type cancer cells. Given that TGFβ is a known driver of epithelial to mesenchymal transition (EMT), and the connection between EMT and metastatic spread in EOC and other cancers, we asked if TGFβ and EMT alter the susceptibility of EOC to PARP inhibition. Epithelial EOC cells were transiently treated with soluble TGFβ, and their clonogenic potential, expression, and function of EMT and DNA repair genes, and response to PARP inhibitors compared with untreated controls. A second epithelial cell line was compared to its mesenchymal derivative for EMT and DNA repair gene expression and drug responses. We found that TGFβ and EMT resulted in the downregulation of genes responsible for homologous recombination (HR) and sensitized cells to olaparib. HR efficiency was reduced in a dose-dependent manner. Furthermore, mesenchymal cells displayed sensitivity to olaparib, cisplatin, and the DNA-PK inhibitor Nu-7441. Therefore, the treatment of disseminated, mesenchymal tumors may represent an opportunity to expand the clinical utility of PARP inhibitors and similar agents.

Uncovering miRNA–mRNA Regulatory Networks Related to Olaparib Resistance and Resensitization of BRCA2MUT Ovarian Cancer PEO1-OR Cells with the ATR/CHK1 Pathway Inhibitors

“…SMAD2 gene, targeted by three DE miRNAs, was found to be enriched in the pathways controlled by TGFβ receptors. Findings by Roberts et al revealed that treatment with TGFβ induced EMT and downregulated homologous recombination repair protein, resulting in resensitization of HGSOC cells to olaparib in vitro [61]. Here, we showed that enriched signaling by FGFR1, EGFR, PDGF as well as VEGFR2 mediated cell proliferation was associated with genes encoding trinucleotide repeat-containing gene 6A protein (TNRC6A) and calmodulin 1 (CALM1), targeted by three and two DE miRNAs, respectively.…”

Shake It Up Baby Now: The Changing Focus on TWIST1 and Epithelial to Mesenchymal Transition in Cancer and Other Diseases

“…Recent studies in breast and ovarian cancer have shown that EMT can, in certain circumstances, be a marker of drug sensitivity rather than resistance. As we and our colleagues recently observed, in ovarian cancer this may be a case of stemness and EMT working in opposite directions, with both very epithelial and very mesenchymal cells exhibiting drug resistance [119] (Figure 3). Furthermore, how mesenchymal markers correspond to therapeutic efficacy in sarcomas remains to be seen.…”

“…Despite the many cases described here in which EMT or its constituent transcription factors are associated with drug resistance, there are some cases in which EMT is a marker of therapeutic vulnerability. For instance, we recently described a reduction in homologous recombination repair protein expression in multiple models of ovarian cancer EMT that sensitized the cells involved to treatment with cisplatin, the PARP inhibitor olaparib, and the DNA-PK inhibitor Nu-7441 [119]. This was based on prior work in which chemoresistant ovarian cancer CSCs were shown to be epithelial, while fast-dividing mesenchymal-like progeny was sensitive [120].…”