Fighting resistance: post-PARP inhibitor treatment strategies in ovarian cancer

Veneziani, Ana; Scott, Clare L.; Wakefield, Matthew J.; Tinker, Anna V.; Lheureux, Stéphanie

doi:10.1177/17588359231157644

Cited by 8 publications

(3 citation statements)

References 155 publications

(199 reference statements)

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“…However, resistance to olaparib can develop over time in some patients, necessitating a critical understanding of associated mechanisms. Indeed, multifactorial mechanisms of resistance to PARPi and platinum analogs were demonstrated to be at least partially interrelated in OC cells [8,39]. Recent studies have demonstrated that modulators of DNA damage response, including the ATR/CHK1 pathway inhibitors, can resensitize OC cells both in vitro and in vivo [10,39,40].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, multifactorial mechanisms of resistance to PARPi and platinum analogs were demonstrated to be at least partially interrelated in OC cells [8,39]. Recent studies have demonstrated that modulators of DNA damage response, including the ATR/CHK1 pathway inhibitors, can resensitize OC cells both in vitro and in vivo [10,39,40]. Despite extensive research on resistance mechanisms, including epigenetic silencing of gene expression [41], there is still a need to better understand OC desensitization to olaparib, particularly at the post-transcriptional level.…”

Section: Discussionmentioning

confidence: 99%

“…Despite initial effectiveness, the widespread use of olaparib involves an increasing number of patients with acquired resistance and a lack of further approved therapy options [39]. Over recent years, combinations of olaparib with the ATR/CHK1 pathway inhibitors showed promising antitumor activity in OC cells [9,10,40].…”

Section: Discussionmentioning

confidence: 99%

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

Biegała,

Kołat,

Gajek

et al. 2024

Cells

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Resistance to olaparib is the major obstacle in targeted therapy for ovarian cancer (OC) with poly(ADP-ribose) polymerase inhibitors (PARPis), prompting studies on novel combination therapies to enhance olaparib efficacy. Despite identifying various mechanisms, understanding how OC cells acquire PARPi resistance remains incomplete. This study investigated microRNA (miRNA) expression in olaparib-sensitive (PEO1, PEO4) and previously established olaparib-resistant OC cell lines (PEO1-OR) using high-throughput RT-qPCR and bioinformatic analyses. The role of miRNAs was explored regarding acquired resistance and resensitization with the ATR/CHK1 pathway inhibitors. Differentially expressed miRNAs were used to construct miRNA–mRNA regulatory networks and perform functional enrichment analyses for target genes with miRNet 2.0. TCGA-OV dataset was analyzed to explore the prognostic value of selected miRNAs and target genes in clinical samples. We identified potential processes associated with olaparib resistance, including cell proliferation, migration, cell cycle, and growth factor signaling. Resensitized PEO1-OR cells were enriched in growth factor signaling via PDGF, EGFR, FGFR1, VEGFR2, and TGFβR, regulation of the cell cycle via the G2/M checkpoint, and caspase-mediated apoptosis. Antibody microarray analysis confirmed dysregulated growth factor expression. The addition of the ATR/CHK1 pathway inhibitors to olaparib downregulated FGF4, FGF6, NT-4, PLGF, and TGFβ1 exclusively in PEO1-OR cells. Survival and differential expression analyses for serous OC patients revealed prognostic miRNAs likely associated with olaparib resistance (miR-99b-5p, miR-424-3p, and miR-505-5p) and resensitization to olaparib (miR-324-5p and miR-424-3p). Essential miRNA–mRNA interactions were reconstructed based on prognostic miRNAs and target genes. In conclusion, our data highlight distinct miRNA profiles in olaparib-sensitive and olaparib-resistant cells, offering molecular insights into overcoming resistance with the ATR/CHK1 inhibitors in OC. Moreover, some miRNAs might serve as potential predictive signature molecules of resistance and therapeutic response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Biegała,

Kołat,

Gajek

et al. 2024

Cells

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Onvansertib treatment overcomes olaparib resistance in high-grade ovarian carcinomas

Chiappa,

Decio,

Guarrera

et al. 2024

Cell Death Dis

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Occurrence of resistance to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) approved in ovarian carcinoma, has already been shown in clinical settings. Identifying combination treatments to sensitize tumor cells and/or overcome resistance to olaparib is critical. Polo-like kinase 1 (PLK1), a master regulator of mitosis, is also involved in the DNA damage response promoting homologous recombination (HR)-mediated DNA repair and in the recovery from the G2/M checkpoint. We hypothesized that PLK1 inhibition could sensitize tumor cells to PARP inhibition. Onvansertib, a highly selective PLK1 inhibitor, and olaparib were tested in vitro and in vivo in BRCA1 mutated and wild-type (wt) ovarian cancer models, including patient-derived xenografts (PDXs) resistant to olaparib. The combination of onvansertib and olaparib was additive or synergic in different ovarian cancer cell lines, causing a G2/M block of the cell cycle, DNA damage, and apoptosis, much more pronounced in cells treated with the two drugs as compared to controls and single agents treated cells. The combined treatment was well tolerated in vivo and resulted in tumor growth inhibition and a statistically increased survival in olaparib-resistant-BRCA1 mutated models. The combination was also active, although to a lesser extent, in BRCA1 wt PDXs. Pharmacodynamic analyses showed an increase in mitotic, apoptotic, and DNA damage markers in tumor samples derived from mice treated with the combination versus vehicle. We could demonstrate that in vitro onvansertib inhibited both HR and non-homologous end-joining repair pathways and in vivo induced a decrease in the number of RAD51 foci-positive tumor cells, supporting its ability to induce HR deficiency and favoring the activity of olaparib. Considering that the combination was well tolerated, these data support and foster the clinical evaluation of onvansertib with PARPis in ovarian cancer, particularly in the PARPis-resistant setting.

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